Publications

Ioan Alexandru Vacariu¹, Silvia Mihaela Ilie^2,3,4, Cristin Constantin Vere^5,*, Adina Turcu-Stiolica^6,7,*, Eleni Manthopoulou⁸, Mihai Radu Pahomeanu^9,10, Eugen Tcaciuc¹¹, Sebastian Constantin Toma¹², Bogdan Silviu Ungureanu⁵

¹ Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania

² Department of Medical Oncology, Georges Francois Leclerc Cancer Center, 21079 Dijon, France

³ Cancer Biology Transfer Platform, Georges Francois Leclerc Cancer Center, 21079 Dijon, France

⁴ INSERM UMR 1231, Center for Translational and Molecular Medicine (CTM), University of Burgundy Europe, 21079 Dijon, France

⁵ Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania

⁶ Biostatistics Department, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania

⁷ Health Economics and Outcomes Research Department, Faculty of Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Victor Babes Street No. 8, 400012 Cluj-Napoca, Romania

⁸ Gastroenterology Department, General Hospital of Nea Ionia “Konstantopouleio-Patision”, 3–5 Theodorou Konstantopoulou Street, Nea Ionia, 14233 Athens, Greece

⁹ Internal Medicine and Gastroenterology Department, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania

¹⁰ Internal Medicine and Gastroenterology Department, University Emergency Hospital of Bucharest, 050098 Bucharest, Romania

¹¹ Department of Gastroenterology, Nicolae Testemitanu State University of Medicine and Pharmacy, MD-2004 Chisinau, Moldova

¹² General Surgery Department, Dr. Constantin Andreoiu, Ploiesti County Emergency Hospital, 100097 Ploiesti, Romania

* Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(19), 8488

DOI: https://doi.org/10.3390/ijms27198488

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, and reliable prognostic biomarkers are urgently needed to guide risk stratification and treatment. CD74 has been implicated in tumor progression, invasion, and pro-inflammatory signaling in various cancers. This systematic review and meta-analysis aimed to evaluate the association between CD74 expression and key clinicopathological features and survival outcomes in patients with PDAC. A systematic literature search was conducted in PubMed, Web of Science, and Scopus to identify eligible studies reporting on CD74 expression in PDAC tissues (PROSPERO: CRD420261402709). Studies were selected following the PRISMA 2020 guidelines. The methodological quality of the included studies was assessed using the QUIPS tool. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the associations between CD74 expression and perineural invasion (PNI), lymphatic invasion, lymph node metastasis (pN), vascular permeation, pTNM stage, and overall survival. Statistical analyses were performed using Review Manager v5.4. DerSimonian–Laird random-effects models were applied as sensitivity analysis for every outcome, with Mantel–Haenszel fixed-effects models as the primary analysis according to the level of heterogeneity, which was quantified using the I2 statistic. A total of 83 records were initially identified, of which five studies met the inclusion criteria and were included in the quantitative synthesis. CD74-positive expression was significantly associated with an increased risk of perineural invasion (four cohorts, 351 patients; OR = 3.69; 95% CI: 2.27–5.99; p < 0.00001; I2 = 0%), lymphatic invasion (four cohorts, 351 patients; OR = 2.05; 95% CI: 1.21–3.46; p = 0.007; I2 = 0%), and lymph node metastasis (four cohorts, 462 patients; OR = 1.94; 95% CI: 1.27–2.96; p = 0.002; I2 = 0%). A non-significant trend toward increased vascular permeation (three cohorts, 181 patients; OR = 1.99; 95% CI: 0.84–4.68; p = 0.12; I2 = 0%) and advanced pTNM stage (three cohorts, 284 patients; OR = 1.62; 95% CI: 0.93–2.82; p = 0.09; I2 = 0%) was also observed. Importantly, CD74 positivity was significantly associated with worse overall survival (three cohorts, 293 patients; HR = 2.04, 95% CI: 1.45–2.88; p < 0.00001; I2 = 0%). This analysis was structured into two subgroups: HR = 2.21 (95% CI: 1.50–3.25) in the two cohorts contributing multivariable-adjusted, immunohistochemistry-based estimates, and HR = 1.52 (95% CI: 0.72–3.21) in the single cohort contributing a univariable estimate reconstructed from transcript-level data, with no significant difference between the subgroups (p = 0.38). Because the estimated between-study variance was zero for every outcome, random-effects estimates were almost identical to the fixed-effects estimates throughout. As the pooled survival estimate combines adjusted with unadjusted estimates, it describes a prognostic association rather than established independent prognostic value. This meta-analysis demonstrates that elevated CD74 expression in PDAC is significantly associated with perineural invasion, lymphatic invasion, lymph node metastasis, and poorer overall survival, supporting an association with an adverse prognostic. Because the evidence base comprises few retrospective cohorts that used different, non-standardized thresholds to define CD74 positivity and different definitions of several outcomes, these findings should be regarded as hypothesis-generating: they identify CD74 as a candidate for prospective validation and mechanistic investigation rather than as an established biomarker for risk stratification or therapeutic decision-making. Further large-scale prospective studies are warranted to validate these results and explore the clinical utility of CD74-targeted strategies.

Keywords: CD74; pancreatic ductal adenocarcinoma; PDAC; perineural invasion; lymph node metastasis; prognosis; meta-analysis

Chloe Timmins-Young¹, Marco Cordani^2,3, Elisa Giovannetti^4,5, Despoina Aslanoglou⁶, Alvaro Gutierrez^7,3, Eithne Costello^1,9, Mark Glenn^1,8

¹ Liverpool Experimental Cancer Medicine Centre, University of Liverpool, Liverpool, L69 3GE, UK

² Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, Madrid, Spain

³ San Carlos Health Research Institute (IdISSC), Madrid, 28040, Spain

⁴ Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands

⁵ Cancer Pharmacology Lab, Fondazione Pisana per La Scienza, Pisa, San Giuliano Terme, Italy

⁶ School of Medicine, Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK

⁷ Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain

⁸ Technical contact.

⁹ Lead contact.

Email: Eithne Costello — ecostell@liverpool.ac.uk; Mark Glenn — maglenn@liverpool.ac.uk.

DOI: https://doi.org/10.1016/j.xpro.2026.104904

Abstract

Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Highlights
• Steps for generating retrovirus-derived eVLPs for genome editing of PDAC cells
• Instructions for packaging Cas9 RNPs and prime-editing cargos into eVLPs
• Guidance on eVLP transduction of SUIT-2, PANC-1, and MIA PaCa-2 cells
• Instructions for identifying CRISPR/prime editing-mediated indels using PCR

Summary

Pancreatic ductal adenocarcinoma (PDAC) cell lines resist transfection, limiting gene-editing experiments. Here, we present a protocol for delivering CRISPR-Cas9 or prime editors into PDAC cell lines using retrovirus-derived engineered virus-like particles (eVLPs). We describe steps for generating eVLPs, packaging CRISPR-Cas9 ribonucleoproteins or prime editors with engineered prime-editing guide RNAs (epegRNAs), and transducing human PDAC cells. We use the HEK3 locus and NQO1 (NAD(P)H quinone dehydrogenase 1) exon 6 as example edits and controls, respectively. This protocol adapts readily to other genomic sites.

Ioana Creangă-Murariu^1,2,3, Ioana-Irina Rezuș^1,2,4, Roshanak Karami^1,4,5, Amir Makolli^1,6,7, Codrin Chifu⁸, Anett Rancz¹, Zoltán Sipos^9,10, Péter Ferdinandy^6,7,11, Renáta Papp^1,6,7, Brigitta Teutsch^1,12, Bogdan-Ionel Tamba^2,*, Péter Hegyi^1,9,13,14,*, Stefania Bunduc^1,15,16,*

¹ Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary

² Advanced Center for Research and Development in Experimental Medicine “Prof. Ostin C. Mungiu”, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania

³ Medical Oncology-Radiotherapy Department, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania

⁴ Department of Radiology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania

⁵ Pharmacy Faculty, Semmelweis University, 1085 Budapest, Hungary

⁶ Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1085 Budapest, Hungary

⁷ Center for Pharmacology and Drug Research & Development, Semmelweis University, 1085 Budapest, Hungary

⁸ Anesthesiology and Intensive Care Unit, Regional Institute of Oncology, 700483 Iasi, Romania

⁹ Institute for Translational Medicine, Medical School, University of Pécs, 7622 Pécs, Hungary

¹⁰ Institute of Bioanalysis, Medical School, University of Pécs, 7622 Pécs, Hungary

¹¹ Pharmahungary Group, 6722 Szeged, Hungary

¹² Department of Radiology, Medical Imaging Centre, Semmelweis University, 1085 Budapest, Hungary

¹³ Institute of Pancreatic Diseases, Semmelweis University, 1085 Budapest, Hungary

¹⁴ Translational Pancreatology Research Group, Interdisciplinary Centre of Excellence for Research Development and Innovation, University of Szeged, 6720 Szeged, Hungary

¹⁵ Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania

¹⁶ Digestive Disease and Liver Transplant Center, Fundeni Clinical Institute, 022328 Bucharest, Romania

* Authors to whom correspondence should be addressed.

Pharmaceuticals 2026, 19(5), 768

DOI: https://doi.org/10.3390/ph19050768

Abstract

Background: Cannabinoids are studied as anticancer agents, but their effects vary across tumors, compounds, and experimental settings, underscoring the need to define consistent patterns. Our objective was to map cannabinoid efficacy across cancer preclinical models and identify tumor settings with the greatest translational promise.

Methods: The protocol was registered on PROSPERO (CRD42025543744); PubMed, Embase, and CENTRAL were searched on 4 April 2024 for in vitro and in vivo studies assessing cannabinoid antitumor effects alone or with chemotherapy versus vehicle or chemotherapy only. Random-effects models yielded pooled mean differences (MD) with 95% confidence intervals (CI). MDs of viable cells were calculated for in vitro assays and tumor volume (mm3) for in vivo studies. Reports of various compounds, cannabidiol (CBD), tetrahydrocannabinol (THC) or synthetic cannabinoids, were pooled.

Results: We included 189 studies in the final analysis. In vitro, cannabinoids reduced cell viability modestly overall, with significant effects in glioblastoma (MD −18.77 [CI: −27.15; −10.39]) and a nonsignificant trend in breast cancer (MD −6.75 [CI: −13.90; 0.40]). For in vivo, monotherapy showed the most consistent efficacy in glioblastoma, significantly reducing tumor volume by MD −980.58 mm3; [CI: −1270.2; −690.88]. Addition to temozolomide produced a favorable but nonsignificant decrease of MD −220.65 mm3; [CI: −579.34; 138.03, vs. temozolomide]. In breast cancer, cannabinoids achieved smaller yet significant tumor reductions (MD −402.64 mm3); [CI: −671.84; −133.45]. Synthetic agents had the largest effect (MD −1295.19 mm3); [CI: −1664.33; −928.05] -CBD plus doxorubicin vs. doxorubicin). Lung cancer (MD −562.17 mm3); [CI: −693.99; −430.35] and prostate cancer (MD −1136.59 mm3); [95% CI: −1320.97; −952.21] also had a significant response, whereas colon, pancreatic, and hepatocellular carcinoma models showed inconsistent or null responses.

Conclusions: Cannabinoids show promise as adjuncts in oncotherapy, particularly in glioblastoma and breast cancer, to enhance chemotherapy efficacy. These findings should be interpreted with caution given the high inter-study heterogeneity typical of preclinical research and should be considered hypothesis-generating, warranting further validation in standardized and clinically relevant models.

Keywords: cannabinoids; antitumor effects; glioblastoma; breast cancer; preclinical studies

Aitor González-Titos^1,2,3,4, Belén Toledo^1,2,5, Sonakshi De^4,6, María José Grande¹, Antonio Gálvez¹, Juan Antonio Marchal^2,3,7,8, Diethard Mattanovich^4,6, Macarena Perán^1,2,3

DOI: https://doi.org/10.1186/s12934-026-03019-5

Abstract

Background
Trypsinogen and chymotrypsinogen are serine proteases with potential therapeutic applications in cancer. However, due to ethical, safety and variability concerns, their clinical use has been limited by the reliance on bovine or porcine pancreatic extracts. Recombinant expression in Komagataella phaffii (syn. Pichia pastoris) offers a scalable and controlled alternative. However, further optimisation is required to increase protein titer and secretion.

Results
Recombinant strains were engineered to express human trypsinogen and chymotrypsinogen. The effect of medium supplementation and co-expression of HAC1 and PDI1 on protein production was evaluated. Co-expression of HAC1 increased trypsinogen production by 3.2-fold, while PDI1 significantly increased chymotrypsinogen titer by 8.5-fold compared to parental strains. Medium optimisation had minimal effect on protein expression. SDS-PAGE and Western blotting analyses confirmed successful expression and secretion of both enzymes.

Conclusions
The combination of genetic modification and medium optimisation significantly improved the recombinant production of trypsinogen and chymotrypsinogen in K. phaffii. HAC1 proved to be more effective in increasing the production of trypsinogen, while PDI1 co-expression significantly increased chymotrypsinogen titers. These findings provide a promising strategy for improving the production of these proteases, supporting their potential applications in biotechnology and biomedical research.

Pablo Hernández-Camarero^1,2, Belén Toledo^2,3,8, Ana Belén Díaz-Ruano^1,2, Manuel Picon-Ruiz^1,2,6,7, Aitor González-Titos^1,2, Roberto Madeddu^3,4,5, Juan Antonio Marchal^1,2,6,7, Macarena Perán^2,6,8

DOI: https://doi.org/10.1186/s12967-026-08216-9

Abstract

Background
Although the crosstalk between the immune system and tumour endothelial cells has been extensively investigated, interactions with tumour-associated pericytes (TAPs) remain poorly understood. Such issue may be of great interest considering the immunoregulatory roles of pericytes reported in both healthy and tumour tissues. This systematic review integrates current evidence on TAP–immune system interplay, encompassing functional roles, molecular mechanisms, associated biomarkers, and in vitro assessment methodologies. Preclinical investigations on the anticancer potential of TAP-targeted immunotherapies were also critically analysed, complemented by a meta-analysis assessing TAP-mediated immune regulation across distinct malignancies with a larger sample size.

Methods
Following the 2020 PRISMA guidelines, literature searches were conducted in PubMed, Web of Science, and Scopus for studies published up to February 2026. Of 3,557 records, 64 met the inclusion criteria after multi-stage screening (“title and abstract,” “full text” and “reference check”). Risk of bias was assessed using the OHAT tool for in vitro studies and the SYRCLE tool for in vivo research. Meta-analyses were performed using UALCAN and TIMER platforms.

Results
Our findings identified tumour-associated macrophages (TAMs) as the main immune regulators of TAPs, while TAPs modulate a broad range of immune cells—including TAMs, dendritic cells, B and T lymphocytes, regulatory T cells, myeloid-derived suppressor cells, and natural killer cells—thereby promoting an immunosuppressive tumour microenvironment. Indeed, experimental studies demonstrate the capacity of TAPs to reduce the anti-tumour efficacy of traditional cancer immunotherapies like inhibitory immune checkpoint blockade or adoptive immune cells therapies. Evidence remains scarce for certain cancers (e.g., cholangiocarcinoma, hepatic, and head and neck squamous cell carcinoma) and for lymphatic TAPs. Marked heterogeneity among TAPs and the limited availability of commercial pericyte-like cell lines represent major experimental challenges. Immunotherapies targeting TAPs, such as cancer vaccines and CAR-engineered immune cells, showed promising preclinical efficacy, highlighting their potential as translational medicine. Our meta-analysis further supports the strong immunosuppressive potential of TAPs, even in the underexplored malignancies above mentioned.

Conclusions
Collectively, this study highlights the crucial interplay between TAPs and immune cells in tumour biology and underscores the therapeutic promise of TAP-targeted immunotherapies, along with the importance of long-term evaluation of TAP-targeted immunotherapies and the development of standardized pericyte-like cell models.

Trial registration
The section “Immunotherapies Targeting TAPs” was registered in PROSPERO (ID: CRD420251053567).

Lucie Petrásková, Michael Kotik, Natalia Kulik, Andrea Vopálenská, Anna Šidáková, Katerina Brodsky, Vladimír Křen, Pavla Bojarová^*

DOI: https://doi.org/10.1021/acs.jafc.6c02816

Abstract

Rutinosidases (α-l-rhamnosyl-β-d-glucosidases) are glycosidases (EC 3.2.1.168) that cleave the glycosidic bond between the aglycone and the disaccharide residue rutinose. Their dual substrate specificity is reflected in their activity toward both rutin (rutinosylated) and isoquercitrin (glucosylated) substrates. The structure of rutinosidase from Aspergillus niger (AnRut) features a side tunnel that influences the enzyme hydrolytic and transglycosylation activities. We present a mutagenesis study of this side tunnel, and the compartment forming the +1 binding subsite, resulting in seven variants with different active-site entry geometries. We show that the key side tunnel residues affect the catalytic and trans-rutinosylation potential of AnRut and compare these properties with rutinosidase from Aspergillus oryzae, which has a side groove instead of a side tunnel. The trans-rutinosylation abilities of the enzymes were tested using a diverse library of acceptors. This work expands the structure–function understanding of fungal rutinosidases and underlies the hypothesis that the engineering of the side tunnel can increase the transglycosylation-to-hydrolysis ratio.uation.

Sonia Hermoso-Durán^1,2,3,4, David Ortega-Alarcon^1,2, Astrid Z. Johansen⁵, Mattew J. McKay⁶, Julia S. Johansen^5,7,8, Sonia Vega¹, Claus L. Feltoft⁷, Troels Gammeltoft Dolin^7,8, Jakob Lykke⁹, Nicolas Fraunhoffer¹⁰, Oscar Sanchez-Gracia¹¹, Pablo F. Garrido^1,12,13, Ángel Lanas^2,3,14,15, Mark P. Molloy⁶, Adrian Velazquez-Campoy^1,2,3,16, Olga Abian^1,2,3,16,17

¹ Institute of Biocomputation and Physics of Complex Systems (BIFI), Universidad de Zaragoza, Zaragoza, 50018, Spain

² Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, 50009, Spain

³ Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, 28029, Spain

⁴ Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

⁵ Department of Oncology, Copenhagen University Hospital – Herlev and Gentofte, Herlev, 2730, Denmark

⁶ School of Medical Sciences, Kolling Institute, The University of Sydney, St Leonards, NSW, Australia

⁷ Department of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Herlev, 2730, Denmark

⁸ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark

⁹ Department of Surgery, Copenhagen University Hospital – Herlev and Gentofte, Herlev, 2730, Denmark

¹⁰ Aix-Marseille Université, CNRS, Equipe labélisée Ligue Nationale Contre le Cancer, Centre Interdisciplinaire de Nanoscience de Marseille, Marseille, 13288, France

¹¹ Departamento de Ingeniería Electrónica y Comunicaciones, Universidad de Zaragoza, Zaragoza, 50009, Spain

¹² Department of Physics, University of Oslo, Oslo, 0316, Norway

¹³ Center for Lifespan Changes in Brain and Cognition, University of Oslo, Oslo, 0316, Norway

¹⁴ Hospital Clínico Universitario Lozano Blesa, Avenida San Juan Bosco 13, Zaragoza, 50009, Spain

¹⁵ Departamento de Medicina, Psiquiatría y Dermatología, Universidad de Zaragoza, Zaragoza, 50009, Spain

¹⁶ Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, 50009, Spain

¹⁷ Lead contact.

Email: Adrian Velazquez-Campoy — adrianvc@unizar.es; Olga Abian — oabifra@unizar.es.

Received: September 4, 2025; Revised: December 12, 2025; Accepted: December 17, 2025; Published online: January 21, 2026

DOI: https://doi.org/10.1016/j.isci.2026.114751

Abstract

Highlights

•Thermal liquid biopsy improves early detection of colorectal cancer
•Integrating TLB with clinical data improves diagnosis, especially in stages I–III CRC
•Proteomics identifies FGL1 as a novel serum biomarker linked to prognosis
•Combining TLB, clinical data, and proteomics supports non-invasive, personalized diagnosis

Summary

Early detection of colorectal cancer is essential to improving survival, where yet current diagnostic tools show limited performance. This study aimed to enhance diagnostic accuracy by integrating clinical variables with thermogram profiles obtained through serum-based thermal liquid biopsy and analyzed using machine learning models. We evaluated 328 patients with colorectal cancer and 355 symptomatic individuals with non-organ-specific cancer signs but negative diagnostic evaluations, to reproduce clinically relevant decision settings. The combined model showed improved classification performance compared with the use of clinical variables alone, particularly in patients with early-stage disease. In addition, proteomic analysis of samples stratified by thermogram patterns identified proteins associated with survival, including fibrinogen-like protein 1, supporting the biological relevance of these thermodynamic profiles. Together, these findings indicate that integrating serum thermogram information with routine clinical data can modestly strengthen diagnostic assessment and help identify biologically meaningful patient subgroups, offering a promising non-invasive colorectal cancer evaluation.

Laura Drndakova¹, Lucia Juhasikova¹, Ivana Hlavenova¹, Verona Buocikova¹, Sara Durdiakova², Michal Mego², Milan Buc³, Bozena Smolkova¹

DOI: https://doi.org/10.1186/s13148-026-02081-5

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, primarily due to its highly fibrotic and immunosuppressive tumor microenvironment (TME), which limits both drug delivery and immune cell infiltration. Epigenetic dysregulation plays a pivotal role in shaping these barriers by controlling transcriptional programs that govern tumor-immune interactions, stromal remodeling, and immune evasion.

This review synthesizes current insights into the contribution of aberrant epigenetic mechanisms to PDAC progression and immune resistance. We outline how epigenetic alterations suppress antigen presentation, sustain immunosuppressive cell populations, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and upregulate immune checkpoint molecules across cancer and stromal compartments. Emerging evidence shows that epigenetic therapies targeting DNA methyltransferases, histone deacetylases, histone methyltransferases, or bromodomain proteins can restore tumor immunogenicity, reprogram cancer-associated fibroblasts, and promote cytotoxic T cell infiltration. Furthermore, combining epigenetic modulators with immune checkpoint blockade or targeted therapies has demonstrated the capacity to remodel the PDAC TME and convert immunologically ‘cold’ tumors into more responsive ones. Therefore, we also summarize key completed and ongoing clinical trials in PDAC and solid tumors, emphasizing outcomes and biomarker discoveries that support the translation of epigenetic-immunotherapy combinations into clinical practice. Finally, we discuss persistent challenges that impede progress, including poor drug penetration through the desmoplastic stroma, off-target effects and toxicity of epigenetic agents, tumor hypoxia, adaptive resistance, and the scarcity of physiologically relevant immuno-oncology models.

Findings from preclinical and early clinical studies indicate that epigenetic reprogramming represents a promising avenue to overcome PDAC immunoresistance by reactivating antigen presentation, disrupting immunosuppressive cellular networks, and enhancing antitumor immunity. However, realizing this potential will require rationally designed combination regimens, predictive biomarkers for patient stratification, and a deeper understanding of cell type-specific and context-dependent epigenetic regulation. Only through these advances can the integration of epigenetic modulation with immunotherapy and stroma-targeting approaches ultimately redefine therapeutic strategies for patients with PDAC.

Juan Deng^1,2, Giulia Lencioni^3,4, Aldo Pastore^3,4, Adam E. Frampton^5,6, Dongmei Deng⁷, Elisa Giovannetti^1,2,8

DOI: https://doi.org/10.1186/s13148-026-02163-4

Abstract

Background
Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate due to late-stage diagnosis. Although SUIT2 sublines differ in metastatic and drug-resistant behavior, the mechanisms behind these differences are unclear. Fluid shear stress can regulate tumor cell migration, and the mechanosensitive factor yes-associated protein (YAP) promotes PDAC progression. However, the impact of shear stress on YAP signaling in PDAC cells remains unknown. This study aims to better understand how fluid shear stress influences the behavior of PDAC cells and to elucidate the mechanisms by which shear stress regulates their metastatic potential, in order to support the development of more effective therapeutic strategies.

Results
Using the BioFlux-Shear-Flow-System, we observed that under static conditions, the more metastatic SUIT2-007 cells displayed greater migratory capacity than the less metastatic SUIT2-028 cells. However, exposure to fluid shear stress significantly enhanced the migration capacity of SUIT2-028 cells. Consequently, the migratory capacities of the two cell lines became comparable under shear stress conditions. RNA-sequencing revealed differences in yes-associated protein (YAP) activation between SUIT2-028 and SUIT2-007. Functional assays using a YAP activation inhibitor and scratch assay demonstrated that inhibition of YAP activity reduced migration in both tumor cell lines and abolished the differences in their migratory capacities.

Conclusions
Our findings highlight YAP as a mechanosensitive regulator of pancreatic cancer cell migration under shear stress, offering insights into how biomechanical forces can drive metastatic capacity.

Jázmin Németh^1,2, Jimin Lee¹, Orsolya Eperjesi^1,3,4, Endre Botond Gagyi^1,5,6, Zoltán Bánfalvi^1,4, Veronika Lillik^1,7, Ioana Creanga-Murariu^1,8, Réka Tóth¹, Eszter Ágnes Szalai^1,9, Mahmoud Obeidat¹, Szilárd Váncsa^1,4, Stefania Bunduc^{1,2,10,11,*,†}, Péter Hegyi^1,2,4,12,†

¹ Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary

² Institute for Translational Medicine, Medical School, University of Pécs, 7622 Pécs, Hungary

³ Department of Internal Medicine, Toldy Ferenc Hospital, 2700 Cegléd, Hungary

⁴ Institute of Pancreatic Diseases, Semmelweis University, 1085 Budapest, Hungary

⁵ Department of Medical Imaging, Bajcsy-Zsilinszky Hospital and Clinic, 1106 Budapest, Hungary

⁶ Selye János Doctoral College for Advanced Studies, Semmelweis University, 1085 Budapest, Hungary

⁷ Fejér County Szent György University Teaching Hospital, 8000 Székesfehérvár, Hungary

⁸ Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 700454 Iasi, Romania

⁹ Department of Restorative Dentistry and Endodontics, Semmelweis University, 1085 Budapest, Hungary

¹⁰ Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania

¹¹ Digestive Disease and Liver Transplant Centre, Fundeni Clinical Institute, 022328 Bucharest, Romania

¹² Translational Pancreatology Research Group, Interdisciplinary Centre of Excellence for Research Development and Innovation, University of Szeged, 6720 Szeged, Hungary

* Author to whom correspondence should be addressed.

† These authors contributed equally to this work.

DOI: https://doi.org/10.3390/cancers18071108

Abstract

Background/Objectives: Cardiovascular diseases (CVDs) frequently limit the feasibility and effectiveness of cancer treatment. However, CVD burden has not been comprehensively described in pancreatic cancer. In our systematic review and meta-analysis, we evaluated the prevalence and incidence of CVDs in pancreatic ductal adenocarcinoma (PDAC). Methods: We conducted the systematic search in PubMed, EMBASE, and CENTRAL on 5 February 2024. Studies reporting the prevalence or incidence of CVDs in PDAC were included. Subgroup analyses were performed based on cancer stage and treatment type. Pooled proportions with the 95% confidence interval (CI) were calculated using a random-effects model. (PROSPERO: CRD42023482295). Results: We included 197 articles. At PDAC diagnosis, non-thrombotic cardiovascular diseases (NT-CVDs) were as prevalent as in the general population: hypertension in 33% (CI: 27–40%), ischemic heart disease in 6% (CI: 3–12%), and heart failure, arrhythmia, and stroke each in 2–3%. Their incidence during treatment remained low (1–10%). Thrombotic events, excluding pulmonary embolism, were present in 11% (CI: 7–15%) at diagnosis, with an incidence of 8–10% regardless of stage or treatment. Pulmonary embolism affected 3% at diagnosis and occurred at a similar rate during treatment. Conclusions: Thromboembolic events are common in PDAC and occur both at diagnosis and during follow-up. Their incidence remains stable across treatment modalities and disease stages, suggesting that the tumor itself is the primary driver of thrombotic risk. The prevalence of NT-CVDs in PDAC is comparable to that in the general population and shows minimal variation across cancer stages or treatment modalities.

Keywords

pancreatic cancer; cardio-vascular events; thromboembolism; meta-analysis

Marco Pagano Mariano^1,2,#, Enrica Sgarilli^2,3,#, Dirk Mijnlieff³, Bonifiya Visuvasam³, Andrea Blesio^2,3, Graziana Digiacomo², Andrea Cavazzoni², Manuela Ferracin^1,4, Elisa Giovannetti^3,5

DOI: https://doi.org/10.20517/cdr.2026.52

Abstract

Oncogenic KRAS mutations are a defining feature of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal solid malignancies, characterized by poor responsiveness to chemotherapy. Recent clinical successes of direct KRAS inhibitors in other cancer types have renewed interest in KRAS-directed therapy for PDAC. However, early clinical experience has revealed often short-lived responses, highlighting the rapid emergence of resistance and the need to understand the mechanisms limiting durable benefit. This review summarizes current knowledge on molecular resistance to RAS-directed inhibitors in PDAC, organized into five categories: intrinsic resistance, KRAS-dependent mechanisms, KRAS-independent bypass signaling, downstream pathway reactivation, and tumor microenvironment (TME)-mediated resistance. Evidence from PDAC models is integrated with insights from other KRAS-driven malignancies, particularly non-small cell lung cancer, where direct KRAS inhibition has been studied extensively. Collectively, resistance appears to arise from layered adaptive processes rather than single alterations, including secondary KRAS mutations, receptor tyrosine kinase-driven bypass signaling, reactivation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, stromal-mediated protection, and reduced drug exposure. Notably, until recently, most evidence in PDAC has been indirect, while direct investigation of resistance mechanisms in KRAS-targeted settings has expanded rapidly only in recent years. Building on these advances, ongoing clinical trials increasingly explore rational combination strategies targeting upstream regulators, downstream effectors, and the TME. However, critical challenges persist, including patient selection, treatment sequencing, toxicity, and the lack of pharmacodynamic frameworks. Overcoming resistance will require mechanistically guided combinations, improved disease-specific models, and biomarker-driven adaptive strategies to ultimately achieve durable clinical benefits in PDAC.

Keywords

PDAC
G12D
G12V
EMT
tumor microenvironment
autophagy
Hippo pathway
MAPK pathway

Daniela Mercedes D’Empaire Altimari, Michele Bevere, Elisa Espinet, Yvan Martineau, Elisa Giovannetti & Víctor Javier Sánchez-Arévalo Lobo

PMID: 41796340

DOI: https://doi.org/10.1186/s12943-026-02614-9

Mol Cancer. 2026 Mar 9.

Giulia Peduzzi, Roberto Pellungrini, Livia Archibugi, Federico Canzian, Cosmeri Rizzato, Gabriele Capurso, Daniele Campa

DOI: https://doi.org/10.1002/ueg2.70102

Abstract

Background
The incidence of pancreatic ductal adenocarcinoma (PDAC) is lower in females than males (19.0 vs. 20.2 for 100,000 individuals in Europe). This disparity is commonly attributed to differences in exposure to lifestyle risk factors such as smoking and alcohol consumption; however, hormonal activity may also play a role.

Objective
This study aimed to comprehensively examine the role of hormone exposure and reproductive factors in males and females in PDAC susceptibility.

Methods
We analyzed 816 PDAC cases and 302,645 controls from the UK Biobank prospective cohort. Twenty hormone-related variables and a polygenic risk score (PRS) were examined in females and males using epidemiological methods and machine learning algorithms.

Results
Oral contraceptives (OC) use increased PDAC risk (OR = 2.17 (95% CI: 1.70–2.80), p = 8.16 × 10−10), while each full-term pregnancy decreased it (OR = 0.83 (95% CI: 0.76–0.90), p = 2.60 × 10−5). In males increased level of sex hormone-binding globulin (SHBG) was associated with a decreased risk (OR = 0.98, 95% CI: 0.97–0.98, p = 7.38 × 10−10). The machine learning model performed well in both sexes, with AUCs of 0.95 and 0.92, specificity of 0.86 and 0.92 and sensitivity of 0.90 and 0.81 for females and males, respectively. The use of an explainer identified age and the PRS as significant features for both sexes, with additional factors such as age at menopause and OC use for females, and SHBG concentration in blood for males.

Conclusion
We observed a consistent protective effect of the factors that decrease-the exposure to menstrual cycle related hormones. Additionally, exogenous hormones increase due to long exposure to OC and HRT increases the risk of the disease. Therefore, our result suggests that it is more important to which hormones an individual is exposed compared to the overall increase or decrease in exposure.

Bogdan Silviu Ungureanu¹, Dan Ionut Gheonea¹, Adina Turcu-Stiolica², Michael Schenker³, Daniel Pirici⁴, Cristin-Constantin Vere¹, Andrei Fierut⁵, Adrian Saftoiu⁶

DOI: https://doi.org/10.1186/s13287-025-04601-1

Abstract

Recent evidence suggests that EpCAM and CD44 could serve as diagnosis or prognosis markers in pancreatic cancer (PC). In this meta-analysis, we evaluated their associations with clinicopathologic features. Specifically, we compared immunohistochemical-positive and -negative PC patients for T stage (T3-T4 vs. T1-T2), N stage (N1 vs. N0), M stage (M1 vs. M0), tumor grade (well/moderately vs. poorly differentiated), UICC Stage (III, IV vs. I, II), and overall survival (OS). The diagnostic meta-analysis was performed analysing the pooled sensitivity and specificity and evaluating overall accuracy to indicate the diagnostic efficacy of the markers. The protocol of this systematic review and meta-analysis was registered on the PROSPERO website under the registration number of CRD42024568390. A systematic search of PubMed, Scopus, and ISI Web of Science was conducted on January 30th, 2025. The statistical analysis was performed using the Review Manager 5.4 software and R language (R package Mada and Metafor). The quality of the studies included was assessed using the Newcastle-Ottawa scale and the QUADAS-2 tool. Data from relevant studies were independently screened and extracted using Rayyan, by at least two authors. A total of 19 studies were eligible (9 studies for EpCAM, 9 studies for CD44, and 2 studies for both EpCAM and CD44), comprising a total of 1370 patients. The diagnostic meta-analysis demonstrated moderate accuracy for EpCAM (AUC, 95% CI of 0.802, 0.69–0.96). A statistically significant association was found for CD44 expression and T-status (OR = 2.04, 95%CI = 1.18–3.51), or N-stage (OR = 2.68, 95%CI = 1.86–3.85), or TNM stage (OR = 3.79, 95%CI = 2.14–6.71). CD44v6 overexpression predicted worse OS (HR = 2.33, p < 0.00001), while EpCAM + CD44 + co-expression was prognostic (HR = 2.02, p = 0.02). Heterogeneity was not observed among the studies included, but further research is warranted to better understand the clinical implications of these markers’ positivity in PC diagnosis and prognosis.

Similar content being viewed by others

Jiajia Tang^1,2,16,17, Quan Zheng^1,2,16, Qi Wang^1,2,16, Yaru Zhao^1,2, Preeta Ananthanarayanan³, Chiara Reina³, Berina Šabanović³, Ke Jiang^1,2, Ming-Hsin Yang⁴, Clara Csilla Meny⁵, Huimin Wang^1,2, Mette Ø. Agerbaek^6,7, Thomas Mandel Clausen⁶, Tobias Gustavsson^6,8, Chenlei Wen^9,10,11, Felice Borghi¹², Alfredo Mellano¹², Elisabetta Fenocchio¹³, Vanesa Gregorc¹³, Anna Sapino¹⁴, Thor G. Theander⁶, Da Fu^9,10,11, Alexandra Aicher¹⁵, Ali Salanti⁶, Baiyong Shen^9,10,11, Christopher Heeschen^1,2,3,18

Email: Jiajia Tang — jiajia.tang@shsmu.edu.cn; Christopher Heeschen — christopher.heeschen@icloud.com.

DOI: https://doi.org/10.1016/j.xpro.2025.103635

Abstract

Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Highlights

• Approach for the efficient capture of circulating tumor cells (CTCs) from blood
• Steps for establishing long-term 3D organoid cultures from CTCs
• Guidelines for utilizing CTC-derived cultures in functional drug screening

Summary

We introduce a protocol for generating 3D organoids from circulating tumor cells (CTCs), enabling longitudinal functional and molecular analyses in pancreatic cancer patients, including those with unresectable disease, which constitutes the majority of cases. We outline the process for isolating and characterizing CTCs from the blood of pancreatic cancer patients and provide detailed instructions for initiating, passaging, and phenotyping CTC-derived organoids. Additionally, we describe techniques for utilizing these organoids in drug screening with a focus on stemness-related pathways.
For complete details on the use and execution of this protocol, please refer to Tang et al.1

Belén Toledo^1,2, Aitor González-Titos^1,3, Pablo Hernández-Camarero¹, Elena López-Ruiz^1,3, Carmen Griñán-Lisón^3,4, Elisa Giovannetti^2,5, Juan Antonio Marchal^3,6,7,8, Macarena Perán^1,3,8

DOI: https://doi.org/10.1038/s41598-025-24863-2

Abstract

The tumor microenvironment (TME) plays a pivotal role in tumor initiation, progression, and the formation of pre-metastatic niches. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma containing a significant enriched population of cancer-associated fibroblasts (CAFs). The interplay between CAFs and tumor cells is crucial in driving tumor advancement and metastasis, underscoring the potential benefits of novel therapeutic strategies targeting stromal cells to improve patient survival. Pancreatic (pro)enzymes have shown efficacy in cancer treatment. In this study, we evaluated a formulation of Trypsinogen and Chymotrypsinogen A (PRP) on a model of PDAC-CAFs dynamics. Our findings demonstrated PRP multifaceted effects, including: (i) inhibition of the acquisition of a pro-tumoral phenotype by normal fibroblasts; (ii) enhanced expression of E-cadherin and decreased expression of epithelial-mesenchymal transition (EMT)-associated genes; (iii) blockade of the crosstalk between CAFs and cancer cells, leading to a decrease in the proliferation and migration rate of the pancreatic cancer cells; (iv) modulation of CAFs-induced alteration on endothelial cells; (v) induction of Meflin expression, associated with a less pro-tumoral phenotype; (vi) inhibition of the TGF-β pathway, reducing the activation of Smad2/3 proteins involved in fibroblast phenotypic alteration; (vii) selective induction of apoptosis in CAFs by PRP, as evidenced by increased expression of the BAX biomarker; (viii) impaired fibrotic tissue formation, as tested in an in vivo model of PDAC, by reducing the population of CAFs within the TME. Collectively, these results underscore the potential of PRP as a therapeutic candidate for disrupting the intricate interactions within the PDAC TME. Further research and clinical investigations are necessary to validate the translational potential of PRP as an adjunct therapy for PDAC.

Daisy J.A. Oketch, Matteo Giulietti^*, Francesco Piva^*

Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, Ancona, Italy

* Corresponding authors.

DOI: https://doi.org/10.1016/j.pan.2025.11.001

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent
form of pancreatic cancer and the third leading cause of cancerrelated deaths worldwide. With the advancements in sequencing
technologies, numerous transcriptomic signatures such as coding
(mRNAs) and non-coding RNAs (lncRNAs, miRNAs, circRNAs),
which can be used as prognostic, diagnostic, therapeutic, or
subtype-specific biomarkers have been revealed [1]. Despite this
progress, the lack of a centralized, PDAC-specific, clinically annotated repository of transcriptomic signatures limits their utility in
both research and clinical contexts. To address this, we developed
the Pancreatic cancer Signature COllection for Prognostic Evaluation (PanSCOPE), an online database that consolidates PDACspecific transcriptomic signatures with supporting clinical metadata. PanSCOPE aims to support basic research, single-cell RNA
sequencing (scRNA-seq) data interpretation, and biomarker discovery in PDAC, thereby advancing personalized medicine and
therapeutic development.
We conducted a comprehensive literature search on PubMed to
identify human studies from 2000 to 2025 using combinations of
“pancreatic ductal adenocarcinoma,” “transcriptomic signatures,”
“biomarkers,” and “gene expression.”
Only peer-reviewed primary research articles on human
studies reporting transcriptomic signatures with prognostic significance in PDAC were included, although certain markers may
additionally be associated with diagnostic or therapeutic relevance. Exclusion criteria involved non-PDAC cancers, animal
models, blood-based biomarkers, or studies on previously treated
patients. Techniques considered included bulk RNA-seq, microarrays, and RT-qPCR on patient-derived samples or models such as
patient-derived xenografts (PDXs) or patient-derived organoids
(PDOs).
We annotated the transcriptomic signatures with their potential prognostic and therapeutic relevance along with metadata
including gene identifiers, gene description, expression patterns
(tumor vs normal and short-vs long-term survivors), prognosis,
therapy response, clinicopathological associations, implicated
biological pathways, sample information, and references to the
supporting studies.

Keywords

Pancreatic ductal adenocarcinoma (PDAC); Single-cell RNA sequencing (scRNA-seq); Transcriptomic signatures

Camilla Pecoraro¹, Daniela Carbone^1,*, Fares Hezam Mohammed Al Ostoot^1,2, Mahrou Vahabi², Giulia Lencioni³, Patrizia Diana¹, Elisa Giovannetti^2,3, Barbara Parrino¹

¹ Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy

² Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

³ Cancer Pharmacology Laboratory, Fondazione Pisana per la Scienza, Via Ferruccio Giovannini 13, San Giuliano Terme, 56017 Pisa, Italy

* Author to whom correspondence should be addressed.

DOI: https://doi.org/10.3390/md23080327

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited effective therapeutic options due to late diagnosis, aggressive progression, and rapid development of drug resistance. In pursuit of novel treatments, this study reports the design, synthesis, and biological evaluation of a new series of topsentin derivatives, featuring a 1,2,4-oxadiazole core. The newly synthesized derivatives were screened for antiproliferative activity against multiple PDAC cell lines (SUIT-2, Patu-T, and PANC-1), identifying several compounds with potent growth-inhibitory effects, particularly on SUIT-2 and Patu-T cells. Further studies demonstrated that these compounds also significantly inhibited cell migration and reduced clonogenic potential, with IC50 values in the micromolar range. The results suggest that these marine-inspired 1,2,4-oxadiazole derivatives effectively target key hallmarks of PDAC, including proliferation, migration, and colony formation, supporting their further development as promising candidates for overcoming drug resistance and metastatic progression in pancreatic cancer.

Keywords

1,2,4-oxadiazole; marine alkaloids; heterocycles; topsentin; pancreatic cancer; PDAC; antiproliferative; apoptosis; colony formation assay; drug resistance

Mahrou Vahabi¹, Geng Xu¹, Dzjemma Sarkisjan¹, Btissame El Hassouni¹, Giulia Mantini¹, Valentina Donati², Bing Wang¹, Giulia Lencioni³, Richard J. Honeywell¹, Dongmei Deng⁴, Sabrina Strano⁵, Godefridus J. Peters^1,6, Giovanni Blandino⁵, Elisa Giovannetti^1,3

DOI: https://doi.org/10.1186/s13046-025-03470-z

Abstract

Background
Nucleoside analogues are crucial in treating non-small cell lung cancer (NSCLC), but resistance hampers patient outcomes. The cytidine analogue RX-3117 shows promise in gemcitabine-resistant cancers, yet mechanisms underlying acquired resistance to this drug remain unexplored. This study includes a comprehensive investigation into RX-3117 resistance mechanisms by leveraging new preclinical models and cutting-edge genomic tools, including a CRISPR-Cas9 knockout screen and transcriptomics.

Methods
NSCLC cell lines A549 and SW1573 were exposed to stepwise increasing concentrations of RX-3117 to establish stable resistant subclones, confirmed by SRB and clonogenic assays. Intracellular RX-3117 nucleotide levels were measured via LC/MS-MS, prompting the evaluation and modulation of the expression of key metabolic enzymes by Western blot and siRNA. A CRISPR-Cas9 screen identified genes whose loss increased RX-3117 sensitivity, while RNA-sequencing with differential expression analyses revealed resistance-related pathways, further investigated through cell cycle distribution, knock-out, and ELISA assays.

Results
Resistant clones exhibited decreased accumulation of RX-3117 nucleotides, which however, was not associated to reduced expression of activation enzymes (UCK2, UMPK, CMPK, NME1/NDPK, RR1 and RR2). Instead, increased expression was observed in certain DNA repair and deactivation enzymes (NT5C3) but pharmacological inhibition and silencing of the latter did not circumvent resistance. Remarkably, a comprehensive approach with CRISPR-Cas9 screen highlighted DNA-repair and cell cycle determinants as key sensitizing genes. XL-PCR and RNA-sequencing confirmed aberrations in DNA-repair and pathways involved in cell cycle regulation. Knock-out and pharmacological inhibition validated the role of PKMYT1, a protein kinase involved in G2/M transition and genomic stability. RX-3117-resistant A549 cells showed enhanced sensitivity to the PKMYT1 inhibitor lunresertib and its synergism with RX-3117, suggesting further studies, especially in patients with high PKMYT1 expression who have significantly shorter survival rates, as observed in public databases and validated in an internal cohort of NSCLC patients.

Conclusion
By integrating CRISPR-Cas9 with functional assays and transcriptomics, our study established a framework for decoding resistance mechanisms and highlights potential therapeutic strategies to enhance RX-3117 efficacy in NSCLC. We demonstrated for the first time that aberrant DNA repair and cell cycle dysregulation led resistance, identifying PKMYT1 as a promising target.

Jojanneke Stoof, Charlotte Andrieu, Fiona O’Connell, Jacintha O’Sullivan, Maeve A. Lowery, Naomi Walsh

DOI: https://doi.org/10.1111/jcmm.70816

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited treatment options. PARP inhibitors (PARPi) have shown promise in treating PDAC with homologous recombination deficiency (HRD), but rapid acquisition of resistance limits their efficacy. Our objective is to investigate mechanisms of resistance to PARPi in BRCA2-mutant PDAC cells and identify potential therapeutic targets to modulate this resistance. We developed olaparib- and talazoparib-resistant Capan-1 cell lines and characterised their resistance profiles using viability assays, RNA sequencing and metabolomic profiling. We also developed a cisplatin-resistant Capan-1 cell line to compare resistance mechanisms between PARPi and platinum agents. Both olaparib- and talazoparib-resistant cells showed cross-resistance to other PARPi and oxaliplatin, but not to gemcitabine or 5-FU. Talazoparib-resistant cells exhibited a similar resistance profile to cisplatin-resistant cells, including decreased PARP1 expression and altered metabolomic profiles. RNA sequencing and metabolomic profiling revealed significant enrichment of metabolic pathways, including oxidative phosphorylation and glycolysis, in resistant cells. Our study highlights the complexity of resistance mechanisms to PARPi in PDAC and identifies potential therapeutic targets in metabolism. The differences in the resistance profiles between olaparib and talazoparib suggest that PARP-trapping potency may play a role in resistance development. Further research is needed to validate these findings and explore novel therapeutic strategies to overcome resistance to PARPi in PDAC.

Daniela Carbone, Francesca Terrana, Ludovica Sciuto, Camilla Pecoraro, Geng Xu, Stella Cascioferro, Girolamo Cirrincione, Godefridus J. Peters, Elisa Giovannetti, Barbara Parrino, Patrizia Diana

DOI: https://doi.org/10.1002/cmdc.202500448

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic tumor, is one of the most aggressive and lethal tumor types. Cyclin-dependent kinase 7 (CDK7) has been recently identified as a promising target in multiple human and mouse PDAC preclinical tumor models, due to significant downregulation of gene transcription and preferential inhibition of the mitotic cell cycle. With the aim of finding new CDK7 inhibitors, new indolyl and 7-aza-indolyl pyrazolo [1,5-a]−1,3,5-triazine derivatives are efficiently synthesized and screened for antiproliferative activity against three immortalized cell lines (SUIT 2.28, PATU-T, PANC-1) of PDAC. 8 out of 33 derivatives show remarkable cytotoxicity with IC50 values ranging from 0.19 to 1.58 µM and remarkable inhibition of cell migration from the earliest time point of 4 h, persisting until 24 h. The two most active compounds are further evaluated in clinically relevant models,including gemcitabine-resistant and primary cells (PATU-T GR, PDAC3), confirming their potent activity. They induce apoptosis, upregulate apoptotic gene expression, and disrupt the cell cycle, significantly reducing the viability of spheroidal PATU-T cultures. Additionally, both compounds effectively inhibit CDK7, as demonstrated by an enzyme-linked immunosorbent assay in cell extracts and by a specific enzymatic activity assay.

Eva M. Verdugo-Sivianes^1,2,3,†, Julia Martínez-Pérez^1,4,†, Lola E Navas^1,2, Carmen Sáez^1,5, Amancio Carnero^1,2,*

¹ Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, 41013 Seville, Spain

² CIBERONC, Instituto de Salud Carlos III, 28029 Madrid, Spain

³ Departamento de Ciencias de la Salud y Biomédicas, Facultad de Ciencias de la Salud, Universidad Loyola Andalucía, Avda. de las Universidades s/n, Dos Hermanas, 41704 Sevilla, Spain

⁴ Oncology Department, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain

⁵ Pathology Department, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain

* Author to whom correspondence should be addressed.

† These authors contributed equally to this work.

DOI: https://doi.org/10.3390/cancers17152575

Abstract

Background/Objectives: Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide, with its incidence rising each year. Despite its relatively low incidence, the aggressiveness of pancreatic cancer results in high mortality, with only 12% of patients surviving five years post-diagnosis. Surgical resection remains the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage. The goal of this work is to identify vulnerabilities that can affect the efficacy of treatments and improve the efficacy of therapy. Methods: MAP17 overexpression in pancreatic cancer cell lines, RT-qPCR analysis, xenografts, in vitro and in vivo treatments, analysis of data from pancreatic tumors in transcriptomic patient databases. Results: We studied the prognostic and predictive value of MAP17 (PDZK1IP1) expression in pancreatic cancer, and we found that high MAP17 mRNA expression was associated with poor prognosis. In addition, single-cell analysis revealed that high MAP17 expression was present only in tumor cells. We investigated whether the response to various antitumor agents depended on MAP17 expression. In 2D culture, MAP17-expressing pancreatic cancer cells responded better to gemcitabine and 5-fluorouracil. However, in vivo xenograft tumors with MAP17 expression showed resistance to all treatments. Additionally, MAP17-expressing cells had a high NAD pool, which seems to be effectively depleted in vivo by NAMPT inhibitors, the primary enzyme for NAD biosynthesis. Conclusions: Our findings suggest that MAP17 expression could enhance the prognostic stratification of pancreatic cancer patients. Moreover, the coadministration of NAMPT inhibitors with current treatments may sensitize tumors with high MAP17 expression to chemotherapy and improve the efficacy of chemotherapy.

Keywords

pancreatic cancer; prognosis; MAP17; NAD; biomarkers; chemotherapy

Maria Urbanova^a,1, Fabrice Viol^b,c,1,*, Laura Ruiz-Cañas^d,e,1, Efthymios Koniaris^f,1, Rihards Saksis^g,1, Sandra Batres-Ramos^d,e, Julie Earl^d, Agapi Kataki^h, Verona Buocikova^a, Monika Burikova^a, Marina Cihova^a, Lucia Rojikova^a, Peter Makovicky^a, Miroslava Matuskova^a, Yvonne Kohlⁱ, Andrea Riedmayerⁱ, Marianna Makova^j,k, Ladislav Baciak^j, Daniel Gogola^k, Olesja Rogoza^g, Vita Rovite^g, Bruno Sainz Jr.^d,e,*, Bozena Smolkova^a,2,*, Joerg Schrader^b,2,*

^a Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia

^b Medical Department, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany

^c Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg Eppendorf, 20246, Hamburg, Germany

^d Ramón y Cajal Health Research Institute (IRYCIS), Ramón y Cajal University Hospital. Ctra. Colmenar Viejo, 28034, Madrid, Spain

^e Department of Cancer, Instituto de Investigaciones Biomedicas Sols-Morreale (IIBM), CSIC-UAM, 28029, Madrid, Spain

^f Department of Pathology, Hippokration General, Hospital of Athens, Athens, 11527, Greece

^g Latvian Biomedical Research and Study Centre, Ratsupites Str 1-k1, LV-1067, Riga, Latvia

^h First Department of Propaedeutic Surgery, Hippokration General Hospital of Athens, Athens, 11527, Greece

ⁱ Department Bioprocessing & Bioanalytics, Fraunhofer Institute for Biomedical Engineering IBMT, 66280, Sulzbach, Germany

^j Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia

^k Institute of Measurement Science, Slovak Academy of Sciences, 841 04, Bratislava, Slovakia

* Corresponding authors.

DOI: https://doi.org/10.1016/j.canlet.2025.218033

Abstract

Chemotherapy with cisplatin (CDDP) and etoposide (ETO) is the standard treatment for gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Despite high initial response rates, treatment-related toxicity and acquired resistance remain significant clinical challenges. No molecularly targeted therapies are currently established for this aggressive cancer. Here, we evaluated Aurora kinase inhibition with alisertib (ALI) as a synthetic lethality strategy in ARID1A-deficient GEP-NEC. Subcutaneous and orthotopic xenograft models were established in immunodeficient mice using the GEP-NEC-derived NT-38 cell line, and the therapeutic efficacy of ALI was compared with CDDP + ETO. Tumor responses were assessed by immunohistochemistry, Western blotting, and RNA sequencing. To confirm ARID1A dependency, transient knockdown was induced in the pancreatic neuroendocrine NT-18LM cell line, demonstrating that ALI sensitivity is significantly enhanced in ARID1A-deficient cells. ALI achieved antitumor efficacy comparable to chemotherapy and was well tolerated, with minimal weight loss relative to CDDP + ETO. Distant metastases, an early feature of GEP-NEC, developed in five animals over six weeks, two of which were treated with ALI and three controls. Transcriptomic profiling revealed convergence of both treatments on signal transduction, focal adhesion, receptor tyrosine kinase, and VEGFA-VEGFR2 signaling, while ALI uniquely enriched pathways related to pancreatic secretion, lipid metabolism, protein processing in the endoplasmic reticulum, and extracellular matrix organization. These findings establish Aurora kinase inhibition as mechanistically distinct and selectively effective in ARID1A-deficient GEP-NEC. Given its efficacy, favorable tolerability, and ARID1A-dependent specificity, ALI may represent a promising alternative to platinum-based chemotherapy, offering a strong rationale for further development of mechanism-driven combination strategies for GEP-NEC.

Keywords

Gastroenteropancreatic neuroendocrine carcinoma; ARID1A; Synthetic lethality; Chromatin remodeling; Alisertib

Jakub Červený, Viktoria Heine, Michaela Hovorková, Petr Brož, Eliška Filipová, Natalia Kulik, Martin Hubálek, Josef Cvačka, Lucie Petrásková, Mirane Florencio-Zabaleta, Sandra Delgado, Helena Pelantová, Zuzana Bosáková, Lothar Elling, Jesus Jiménez-Barbero, Ana Ardá, Vladimír Křen, Pavla Bojarová^*

DOI: https://doi.org/10.1021/acs.biomac.5c00377

Martyn Stott^†, Irena Stefanova^†, Lucy Oldfield^*, Anthony Evans^*, James Birch-Ford^*, Rohith Rao^†, William Greenhalf^*, Christopher Halloran^†, Eithne Costello^*

^* Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK

^† Department of Pancreatic Surgery, Liverpool University Hospitals Foundation Trust, Liverpool, UK.

Received: 25 April 2025; Accepted: 12 May 2025

Published online: 11 June 2025

Martyn Stott and Irena Stefanova contributed equally and should be considered first coauthors.

Disclosure: The authors declare that they have nothing to disclose.

This work was supported by Cancer Research UK, grant number C7690/A26881, Pancreatic Cancer UK, and TRANSPAN CA21116. C.H. has funding from NHSE, NIHR and LUHFT.

Reprints: Eithne Costello, PhD, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. Email: ecostell@liverpool.ac.uk.

DOI: https://doi.org/10.1097/as9.0000000000000584

Martin Lovecek^a, Ondrej Strouhal^b, Lenka Cervenkova^c, Simona Susova^c,d, Viktor Hlavac^c,d, Magdalena Chottova Dvorakova^c,e, Petr Holý^c,d, Vaclav Liska^c,f, Pavel Skalický^a, Daniela Skanderova^g, Ales Langer^b, Beatrice Mohelníkova-Duchonova^b,*, Pavel Soucek^c,d,*

^a Department of Surgery, Faculty of Medicine and University Hospital, Palacky University, Olomouc, Czech Republic; ^b Department of Oncology, Faculty of Medicine and University Hospital, Palacky University, Olomouc, Czech Republic; ^c Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; ^d Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic; ^e Department of Physiology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic; ^f Department of Surgery, Faculty of Medicine and University Hospital in Pilsen, Charles University, Pilsen, Czech Republic; ^g Department of Clinical and Molecular Pathology, Faculty of Medicine and University Hospital, Palacky University, Olomouc, Czech Republic

DOI: https://doi.org/10.1016/j.labinv.2025.104205

Lab Invest 105 (2025) 104205

Gianmarco Lazzini  1, Raffele Gaeta  2, Luca Emanuele Pollina  2, Annalisa Comandatore  3  4, Niccolò Furbetta  4, Luca Morelli  4, Mario D’Acunto  5

• PMID:  40247119
• PMCID:  PMC12006465
• DOI:  10.1038/s41598-025-98122-9

Pancreatic ductal adenocarcinoma is currently the 12th most frequent form of cancer worldwide, characterized by a very low 5-year survival rate. Although several therapeutic approaches have been proposed to treat this form of pancreatic cancer, surgical resection is still commonly recognized as the most effective technique to slow down the disease progression and maximize the 5-year survival rate. Analogously, one critical issue is the ability of current diagnostic methodologies to distinguish between irregular growth of the tumor mass and surrounding inflammatory tissues. In this pilot study, we apply Raman spectroscopy, supported by a series of machine learning techniques, to distinguish among healthy, pancreatitis and ductal adenocarcinoma tissues, respectively, for a total of 15 cases. Raman spectroscopy is a label-free, non-destructive spectral technique exploiting Raman scattering. In turn, by applying a combination of principal component analysis and random forest classifier on the Raman spectral dataset, we achieved a maximum accuracy of up to  ∼  96%. Our findings clearly indicate that Raman spectroscopy could become a powerful spectral technique to support pathologists in improving pancreatic cancer diagnosis.

Keywords:  Gaussian Naive-Bayes; Pancreatic ductal adenocarcinoma; Raman spectroscopy; Random forest classifier; SPectral SELection.

© 2025. The Author(s).

https://doi.org/10.1002/ijc.35196

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID_rs9604789 variant with an increased risk of developing the disease (OR_Meta = 1.31, p = 9.67 × 10^-6). We also confirmed the association of TP63_rs1515496 and TP63_rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10^-8 and OR = 1.16, p = 2.74 × 10^-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63_rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10^-4 and p = 1.56 × 10^-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10^-4). These results were in agreement with research suggesting that the TP63_rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

Ylenia Nodari^a,1, Manuel Gentiluomo^a,1, Beatrice Mohelnikova-Duchonova^b, Edita Kreivenaite^c, Anna Caterina Milanetto^d, Jurgita Skieceviciene^c, Stefano Landi^a, Rita T Lawlor^e, Maria Chiara Petrone^f, Paolo Giorgio Arcidiacono^f, Martin Lovecek^g, Maria Gazouli^h, Maarten F. Bijlsma^i,j, Luca Morelli^k, Vytautas Kiudelis^c, Matteo Tacelli^f, Dalila Lucíola Zanette^l, Pavel Soucek^m, Faik Uzunogluⁿ, Rudolf Kaaks^o, Jakob Izbickiⁿ, Ugo Boggi^p, Raffaele Pezzilli^q, Andrea Mambrini^r, Claudio Pasquali^d, Hanneke W. van Laarhoven^s,j, Verena Katzke^o, Giulia Martina Cavestro^t, Cosimo Sperti^u, Martin Loos^v, Anna Latiano^w, Bálint Erőss^x,y,z, Martin Oliverius^aa, Theron Johnson^o, Daniela Basso^ab, John P. Neoptolemos^v, Mateus Nóbrega Aoki^l, William Greenhalf^ac, Pavel Vodicka^ad,ae,af, Livia Archibugi^ag,ah, Giuseppe Vanella^ag,ah, Maurizio Lucchesi^r, Renata Talar-Wojnarowska^ai, Krzysztof Jamroziak^aj, Mohammed Al Saeedi^v, Casper H.J. van Eijck^ak, Juozas Kupcinskas^c, Tamás Hussein^y,z, Marta Puzzono^t, Stefania Bunduc^al,y,z, Mara Götzⁿ, Silvia Carrara^am, Andrea Szentesi^x,an,ao, Francesca Tavano^w, Stefania Moz^ab, Péter Hegyi^x,y,z,ao, Claudio Luchini^e, Gabriele Capurso^ag,ah, Francesco Perri^w, Stefano Ermini^ap, George Theodoropoulos^aq, Giovanni Capretti^ar,as, Orazio Palmieri^w, Laura Ginocchi^r, Niccolò Furbetta^k, Federico Canzian^at, Daniele Campa^a

^a Department of Biology, University of Pisa, Pisa, Italy

^b Department of Oncology, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech Republic

^c Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania

^d Dept. of Surgery, Oncology and Gastroenterology, University of Padova Chirurgia Generale 3, Padova, Italy

^e Department of Diagnostics and Public Health, and ARC-Net Research Centre, University of Verona, Verona, Italy

^f PancreatoBiliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center Vita Salute San Raffaele University San Raffaele Scientific Institute, Milan, Italy

^g Department of Surgery I, University Hospital Olomouc, Olomouc, Czech Republic

^h Laboratory of Biology, Department of Basic Medical Science, School of Medicine, National Kapodistrian University of Athens, Athens, Greece

ⁱ Center for Experimental and Molecular Medicine, Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands

^j Imaging and Biomarkers, Cancer Center Amsterdam, Amsterdam, The Netherlands

^k General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

^l Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba, Brazil

^m Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic

ⁿ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

^o Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

^p Divisione di Chirurgia Generale e dei Trapianti, Università di Pisa, Pisa, Italy

^q Country Medical Association of Potenza, Potenza, Italy

^r Oncological Department, Massa Carrara Azienda USL Toscana Nord Ovest, Carrara, Italy

^s Department of Medical Oncology, Amsterdam UMC, location University of Amsterdam, Amsterdam, The Netherlands

^t Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

^u Deptartment of Surgery, Oncology and Gastroenterology, University of Padova Chirurgia Generale 1, Padova, Italy

^v Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany

^w Division of Gastroenterology, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

^x Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary

^y Center for Translational Medicine, Semmelweis University, Budapest, Hungary

^z Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary

^aa Department of General Surgery, University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic

^ab Department of Medicine-DIMED, Laboratory Medicine-University of Padova, Padova, Italy

^ac Molecular and Clinical Cancer Medicine, The University of Liverpool, Liverpool, United Kingdom

^ad Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic

^ae Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic

^af Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic

^ag Digestive and Liver Disease Unit, S. Andrea Hospital, “Sapienza” University of Rome, Rome, Italy

^ah Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS San Raffaele Scientific Institute, Pancreas Translational and Clinical Research Center, Vita-Salute San Raffaele University, Milan, Italy

^ai Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland

^aj Department of Hematology, Transplantation and Internal Medicine, University Clinical Center of the Medical University of Warsaw, Warsaw, Poland

^ak Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands

^al Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

^am Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy

^an Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary

^ao János Szentágothai Research Center, University of Pécs, Pécs, Hungary

^ap Blood Transfusion Service, Children’s Hospital, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy

^aq First Department of Propaedeutic Surgery, Hippokration General Hospital of Athens, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

^ar Pancreatic Unit, IRCCS Humanitas Research Hospital, Rozzano, Italy

^as Department of Biomedical Sciences, Humanitas University, Milan, Italy

^at Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

¹ These authors contributed equally to this work.

Email: daniele.campa@unipi.it

DOI: https://doi.org/10.1016/j.dld.2023.02.023

Abstract

Background
Early-onset pancreatic cancer (EOPC) represents 5–10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC.

Methods
A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed.

Results
Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69–5.04, P = 1.44 × 10−4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41–65.50, P = 3.58 × 10−4).

Conclusion
In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

Keywords
Pancreatic cancer
Early onset
GWAS
Risk factor

Daniele Campa^a, Manuel Gentiluomo^a, Angelika Stein^b,1, Mateus Nóbrega Aoki^c,1, Martin Oliverius^d,1, Ludmila Vodičková^e,f,g,1, Krzysztof Jamroziak^h,1, George Theodoropoulos^i,1, Claudio Pasquali^j,1, William Greenhalf^k,1, Paolo Giorgio Arcidiacono^l,1, Faik Uzunoglu^m,1, Raffaele Pezzilli^n,1, Claudio Luchini^o,1, Marta Puzzono^p,1, Martin Loos^q,1, Matteo Giaccherini^a,1, Verena Katzke^r,1, Andrea Mambrini^s,1, Edita Kiudeliene^t,1, Kauffmann Emanuele Federico^u,1, Julia Johansen^v,1, Tamás Hussein^w,x,1, Beatrice Mohelnikova-Duchonova^y,1, Casper H.J. van Eijck^z,1, Hermann Brenner^aa,ab,ac,1, Riccardo Farinella^a,1, Juan Sainz Pérez^ad,ae,af,1, Martin Lovecek^ag,1, Markus W. Büchler^q,1, Viktor Hlavac^ah,1, Jakob R. Izbicki^m,1, Thilo Hackert^q,1, Roger Chammas^ai,1, Alessandro Zerbi^aj,ak,1, Rita Lawlor^al,1, Alessio Felici^a,1, Mara Götz^m,1, Gabriele Capurso^am,an,1, Laura Ginocchi^s,1, Maria Gazouli^ao,1, Juozas Kupcinskas^t,1, Giulia Martina Cavestro^p,1, Pavel Vodicka^e,f,g,1, Stefania Moz^ap,1, John P. Neoptolemos^q,1, Lumir Kunovsky^aq,ar,as,1, Stig E. Bojesen^v,1, Silvia Carrara^at,1, Domenica Gioffreda^au,1, Egidijus Morkunas^t,1, Olga Abian^av,1, Stefania Bunduc^x,aw,ax,1, Daniela Basso^ay,1, Ugo Boggi^u,1, Barbara Wlodarczyk^az,1, Andrea Szentesi^ba,1, Giuseppe Vanella^am,an,1, Inna Chen^v,1, Maarten F. Bijlsma^bb,bc,bd,1, Vytautas Kiudelis^t,1, Stefano Landi^a,1, Ben Schöttker^aa,1, Chiara Corradi^a,1, Nathalia Giese^q,1, Rudolf Kaaks^r,1, Giulia Peduzzi^a,1, Péter Hegyi^w,x,ba,be,1, Luca Morelli^bf,1, Niccolò Furbetta^bf,1, Pavel Soucek^ah,1, Anna Latiano^au,1, Renata Talar-Wojnarowska^az,1, Sidsel C. Lindgaard^v,1, Frederike Dijk^bd,bg,1, Anna Caterina Milanetto^j,1, Francesca Tavano^au,1, Klara Cervena^e,f,1, Bálint Erőss^w,x,ba,1, Sabrina G. Testoni^l,1, Judith H.E. Verhagen-Oldenampsen^bh,1, Ewa Małecka-Wojciesko^az,1, Eithne Costello^k,1, Roberto Salvia^bi,1, Evaristo Maiello^bj,1, Stefano Ermini^bk,1, Cosimo Sperti^bl,1, Bernd Holleczek^aa,bm,1, Francesco Perri^au,1, Jurgita Skieceviciene^t,1, Livia Archibugi^am,an,1, Maurizio Lucchesi^s,1, Cosmeri Rizzato^bn, Federico Canzian^b

^a Unit of Genetic, Department of Biology, University of Pisa, Pisa, Italy

^b Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

^c Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute, Oswaldo Cruz Foundation (Fiocruz), Curitiba, Brazil

^d Department of Surgery, University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic

^e Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic

^f Institute of Biology and Medical Genetics, 1st Faculty of Medicine Charles University and General University Hospital in Prague, Prague, Czech Republic

^g Biomedical Centre, Faculty of Medicine in Pilsen Charles University, Pilsen, Czech Republic

^h Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland

ⁱ First Department of Propaedeutic Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens, Athens, Greece

^j Dept. of Surgery, Oncology and Gastroenterology, University of Padova Chirurgia Generale 3, Padova, Italy

^k Liverpool Experimental Cancer Medicine Centre, University of Liverpool, Liverpool, United Kingdom

^l Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientic Institute, Milan, Italy

^m Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

ⁿ Potenza Medica County Association, Potenza, Italy

^o Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy

^p Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy

^q Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany

^r Division of Cancer Epidemiology C020, German Cancer Research Center (DKFZ), Heidelberg, Germany

^s Oncological Department Massa Carrara, Azienda USL Toscana Nord Ovest, Carrara, Italy

^t Institute for Digestive Research and Gastroenterology Department, Lithuanian University of Health Sciences, Kaunas, Lithuania

^u Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy

^v Departments of Oncology and Medicine, Copenhagen University Hospital, Herlev, Denmark

^w Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary

^x Center for Translational Medicine, Semmelweis University, Budapest, Hungary

^y Department of Oncology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

^z Department of Surgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands

^aa Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

^ab Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany

^ac German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

^ad Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain

^ae Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Complejo Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain

^af Department of Immunology, University of Granada, Granada, Spain

^ag Department of Surgery I, University Hospital Olomouc, Olomouc, Czech Republic

^ah Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic

^ai Center for Translational Research in Oncology (LIM24), Departamento de Radiologia e Oncologia, Instituto Do Câncer Do Estado de São Paulo (ICESP), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, Brazil

^aj Pancreatic Unit, IRCCS Humanitas Research Hospital, Milan, Italy

^ak Department of Biomedical Sciences, Humanitas University, Milan, Italy

^al ARC-Net Research Center, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy

^am Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy

^an Digestive and Liver Disease Unit, Sant’ Andrea Hospital, Rome, Italy

^ao Laboratory of Biology, Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens, Greece

^ap Azienda Ospedale-Università di Padova Medicina di Laboratorio, Padova, Italy

^aq Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, Brno, Czech Republic

^ar Department of Gastroenterology and Digestive Endoscopy, Masaryk Memorial Cancer Institute, Brno, Czech Republic

^as 2nd Department of Internal Medicine – Gastroenterology and Geriatrics, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

^at Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy

^au Division of Gastroenterology and Research Laboratory, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

^av Instituto BIFI-Universidad de Zaragoza, Zaragoza, Spain

^aw Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

^ax Center for Digestive Diseases and Liver Transplant, Fundeni Clinical Insitute, Bucharest, Romania

^ay Dept. of Medicine, University of Padova Medicina di Laboratorio, Padova, Italy

^az Dept of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland

^ba Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary

^bb Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands

^bc Oncode Institute, Amsterdam, the Netherlands

^bd Imaging and Biomarkers, Cancer Center Amsterdam, Amsterdam, the Netherlands

^be Translational Pancreatology Research Group, Interdisciplinary Centre of Excellence for Research Development and Innovation University of Szeged, Szeged, Hungary

^bf General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

^bg Department of Pathology, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands

^bh Department of Pulmonary diseases, Erasmus MC University Medical Center, Rotterdam, the Netherlands

^bi Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy

^bj Department of Oncology, Fondazione IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy

^bk Meyer Children’s Hospital IRCCS, Florence, Italy

^bl Dept. of Surgery, Oncology and Gastroenterology, University of Padova Chirurgia Generale 1, Padova, Italy

^bm Saarland Cancer Registry, Saarbrücken, Germany

^bn Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

DOI: https://doi.org/10.1016/j.critrevonc.2023.104020

Abstract

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.

Keywords

Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pancreatic neuroendocrine tumors; Intraductal papillary mucinous neoplasms; Chronic pancreatitis; Genetic epidemiology; Consortium

Federica Anastasi, Asia Botto, Benoit Immordino, Elisa Giovannetti, Liam A. McDonnell

Cytokine & Growth Factor Reviews volume 73, October 2023

https://doi.org/10.1016/j.cytogfr.2023.08.003

The term small extracellular vesicle (sEV) is a comprehensive term that includes any type of cell-derived, membrane-delimited particle that has a diameter < 200 nm, and which includes exosomes and smaller microvesicles. sEVs transfer bioactive molecules between cells and are crucial for cellular homeostasis and particularly during tumor development, where sEVs provide important contributions to the formation of the premetastic niche and to their altered metabolism. sEVs are thus legitimate targets for intervention and have also gained increasing interest as an easily accessible source of biomarkers because they can be rapidly isolated from serum/plasma and their molecular cargo provides information on their cell-of origin. To target sEVs that are specific for a given cell/disease it is essential to identify EV surface proteins that are characteristic of that cell/disease. Mass-spectrometry based proteomics is widely used for the identification and quantification of sEV proteins. The methods used for isolating the sEVs, preparing the sEV sample for proteomics analysis, and mass spectrometry analysis, can have a strong influence on the results and requires careful consideration. This review provides an overview of the approaches used for sEV proteomics and discusses the inherent compromises regarding EV purity versus depth of coverage. Additionally, it discusses the practical applications of the methods to unravel the involvement of sEVs in regulating the metabolism of pancreatic ductal adenocarcinoma (PDAC). The metabolic reprogramming in PDAC includes enhanced glycolysis, elevated glutamine metabolism, alterations in lipid metabolism, mitochondrial dysfunction and hypoxia, all of which are crucial in promoting tumor cell growth. A thorough understanding of these metabolic adaptations is imperative for the development of targeted therapies to exploit PDAC’s vulnerabilities.

The PANcreatic Disease ReseArch (PANDoRA) consortium turns 10! A summary of their main findings can be found in this anniversary paper -> https://doi.org/10.1016/j.critrevonc.2023.104020

Pancreatic disease research (PANDoRA) is dedicated to the identification of pancreatic cancer risk loci and is the largest such consortium in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.

Rebelo R, Xavier CPR, Giovannetti E, Vasconcelos MH.

Trends Mol Med. 2023 Jun;29(6):439-453. doi: 10.1016/j.molmed.2023.03.002. Epub 2023 Apr 24.

PMID: 37100646

https://pubmed.ncbi.nlm.nih.gov/37100646/

Piccardi M, Gentiluomo M, Bertoncini S, Pezzilli R, Erőss B, Bunduc S, Uzunoglu FG, Talar-Wojnarowska R, Vanagas T, Sperti C, Oliverius M, Aoki MN, Ermini S, Hussein T, Boggi U, Jamroziak K, Maiello E, Morelli L, Vodickova L, Di Franco G, Landi S, Szentesi A, Lovecek M, Puzzono M, Tavano F, van Laarhoven HWM, Zerbi A, Mohelnikova-Duchonova B, Stocker H, Costello E, Capurso G, Ginocchi L, Lawlor RT, Vanella G, Bazzocchi F, Izbicki JR, Latiano A, Bueno-de-Mesquita B, Ponz de Leon Pisani R, Schöttker B, Soucek P, Hegyi P, Gazouli M, Hackert T, Kupcinskas J, Poskiene L, Tacelli M, Roth S, Carrara S, Perri F, Hlavac V, Theodoropoulos GE, Busch OR, Mambrini A, van Eijck CHJ, Arcidiacono P, Scarpa A, Pasquali C, Basso D, Lucchesi M, Milanetto AC, Neoptolemos JP, Cavestro GM, Janciauskas D, Chen X, Chammas R, Goetz M, Brenner H, Archibugi L, Dannemann M, Canzian F, Tofanelli S, Campa D.

Biol Res. 2023 Aug 13;56(1):46. doi: 10.1186/s40659-023-00457-y.

PMID: 37574541

https://pubmed.ncbi.nlm.nih.gov/37574541/

Urbanova M, Cihova M, Buocikova V, Slopovsky J, Dubovan P, Pindak D, Tomas M, García-Bermejo L, Rodríguez-Garrote M, Earl J, Kohl Y, Kataki A, Dusinska M, Sainz B Jr, Smolkova B, Gabelova A.

Biomed Pharmacother. 2023 Sep;165:115179. doi: 10.1016/j.biopha.2023.115179. Epub 2023 Jul 21.

PMID: 37481927

https://pubmed.ncbi.nlm.nih.gov/37481927/

Peduzzi G, Felici A, Pellungrini R, Giorgolo F, Farinella R, Gentiluomo M, Spinelli A, Capurso G, Monreale A, Canzian F, Calderisi M, Campa D.

Dig Liver Dis. 2023 Nov 18:S1590-8658(23)01004-6. doi: 10.1016/j.dld.2023.10.015. Online ahead of print.

PMID: 37985251

https://pubmed.ncbi.nlm.nih.gov/37985251/

Vahabi M, Comandatore A, Centra C, Blandino G, Morelli L, Giovannetti E.

Semin Cancer Biol. 2023 Dec;97:50-67. doi: 10.1016/j.semcancer.2023.11.003. Epub 2023 Nov 11.

PMID: 37956937

https://pubmed.ncbi.nlm.nih.gov/37956937/

Alors-Pérez E, Pedraza-Arevalo S, Blázquez-Encinas R, Moreno-Montilla MT, García-Vioque V, Berbel I, Luque RM, Sainz B Jr, Ibáñez-Costa A, Castaño JP

J Exp Clin Cancer Res. 2023 Oct 26;42(1):282. doi: 10.1186/s13046-023-02858-z

PMID: 37880792

PMCID: PMC10601233

https://pubmed.ncbi.nlm.nih.gov/37880792/