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Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 30 November 2025 | Viewed by 11947

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Dr. Donatella Delle Cave

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Institute of Genetics and Biophysics "A. Buzzati Traverso" (IGB-ABT), CNR, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: pancreatic cancer; cancer stem cells; tumor microenvironment; cancer metabolism; fibrosis; TGF-β signaling; target therapy; drug delivery systems
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Dear Colleagues,

Pancreatic cancer (PC) is one of the most aggressive solid malignancies, with an overall 5-year survival rate of ~8%, and it is predicted to become the second leading cause of cancer-related death by 2030. PC progression and metastasis are strongly influenced by metabolic stress imposed by the tumor microenvironment (TME) due to limited oxygen and nutrient supply and unfavorable pH. In this context, deregulation and reprogramming of energy metabolism are hallmarks of PC, which leads tumor cells to rewire their glucose, amino acid, and lipid metabolism on the basis of the bioenergetic and biosynthetic demands needed to survive and escape immunosurveillance. For this reason, exploiting cellular plasticity through targeted reprogramming of metabolic features in PC could lead to the generation of promising and novel selective therapeutic approaches for patients’ treatment.

This Special Issue was set up to encourage researchers to carry out studies on:

Reprogramming of the intracellular metabolism of nutrients (including glucose, amino acids and lipids) to impact PC progression;
Identification of novel pathways underlying metabolic reprogramming as therapeutic targets for PC;
Exploitation of cancer cell plasticity to modulate chemoresistance;
Shaping of the tumor microenvironment to sensitize cancer cells to chemotherapy.

Articles consisting exclusively of bioinformatics or computational analyses of public databases or pure clinical studies will not be accepted. Basic studies or translational studies including molecular characterizations of patients from real practice are welcome. Reviews are also appreciated.

Dr. Donatella Delle Cave
Guest Editor

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Keywords

pancreatic cancer
metabolism
cellular plasticity
tumor microenvironment
target therapy

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Molecular Mechanisms and Therapies of Pancreatic Cancer in International Journal of Molecular Sciences (15 articles)

Published Papers (9 papers)

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Research

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17 pages, 3681 KiB

Open AccessArticle

Sensitivity of Pancreatic Cancer Cell Lines to Clinically Approved FAK Inhibitors: Enhanced Cytotoxicity Through Combination with Oncolytic Coxsackievirus B3

by Anja Geisler, Babette Dieringer, Leslie Elsner, Maxim Girod, Sophie Van Linthout, Jens Kurreck and Henry Fechner

Int. J. Mol. Sci. 2025, 26(14), 6877; https://doi.org/10.3390/ijms26146877 - 17 Jul 2025

Viewed by 160

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by a dense desmoplastic stroma and a highly immunosuppressive tumor microenvironment (TME). The focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is considered a critical regulator of various cellular processes involved in cancer development. FAK inhibitors (FAKi) have proven to be promising therapeutics for cancer treatment including for pancreatic cancer. As monotherapy, however, FAKi showed only a modest effect in clinical studies. In this study, we investigated the cytotoxicity of six FAKi (Defactinib, CEP-37440, VS-4718, VS-6062, Ifebemtinib and GSK2256098) used in clinical trials on five pancreatic tumor cell lines. We further examined whether their anti-tumor activity can be enhanced by combination with the oncolytic coxsackievirus B3 (CVB3) strain PD-H. IC₅₀ analyses identified Defactinib and CEP-37440 as the most potent inhibitors of tumor cell growth. VS-4718, VS-6062, and Ifebemtinib showed slightly lower activity, while GSK2256098 was largely ineffective. The combination of Defactinib, CEP-37440, VS-4718, and VS-6062 with PD-H resulted in varying effects on cytotoxicity, depending on the cell line and the specific FAKi, ranging from no enhancement to a pronounced increase. Using the Chou–Talalay method, we determined combination indices (CI), revealing synergistic, additive, but also antagonistic interactions between the respective FAKi and PD-H. Considering both oncolytic efficacy and the CI, the greatest enhancement in oncolytic activity was achieved when VS-4718 or CEP-37440 was combined with PD-H. These findings indicate that co-treatment with PD-H can potentiate the therapeutic activity of the selected FAKi and may represent a novel strategy to improve treatment outcomes in PDAC. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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24 pages, 3072 KiB

Open AccessArticle

TGFB2 Expression and Methylation Predict Overall Survival in Pancreatic Ductal Adenocarcinoma Patients

by Muhammad Wasif Saif, Wen-Han Chang, Scott Myers, Michael Potts, Sanjive Qazi and Vuong Trieu

Int. J. Mol. Sci. 2025, 26(13), 6357; https://doi.org/10.3390/ijms26136357 - 1 Jul 2025

Viewed by 463

Abstract

Transforming growth factor-beta (TGF-β) exhibits dual roles in pancreatic ductal adenocarcinoma (PDAC), acting as a tumor suppressor in early stages and a tumor promoter in later disease. Among the three isoforms, TGFB2 is particularly associated with poor prognosis and aggressive phenotypes. This study evaluated the prognostic significance of TGFB2 mRNA and methylation levels in PDAC, with an emphasis on age-dependent effects. Bioinformatic analyses revealed that high TGFB2 expression was significantly associated with reduced overall survival (OS) in patients under 65 (TGFB2 high vs. low median OS: 17.9 vs. 66.9 months) but not in older cohorts. IL6 expression, a downstream target of TGF-β, followed a similar survival profile. Moreover, elevated TGFB2 methylation showed improved survival in younger patients (high methylation vs. low methylation median OS: 66.9 vs. 17.9 months). In addition, our clinical data from a PDAC trial using OT-101, an antisense oligonucleotide targeting TGFB2, further supported these findings—young patients treated with OT-101 showed improved OS compared to untreated controls. Notably, the methylation of TGFB1 also correlated with better OS in young patients. These results demonstrate the importance of TGFB2 as both a prognostic biomarker and therapeutic target in younger PDAC patients and further suggest that epigenetic modulation plays a key role in TGF-β signaling in pancreatic cancer progression. Our study emphasizes the isoform- and age-specific prognostic significance of TGFB2 in PDAC and supports the potential insights provided through methylation and expression profiling for personalized treatment strategies, particularly for younger patients who may benefit most from TGFB2-targeted therapies. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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24 pages, 6213 KiB

Open AccessArticle

Transmembrane Protease Serine 11B Modulates Lactate Transport Through SLC16A1 in Pancreatic Ductal Adenocarcinoma—A Functional Link to Phenotype Heterogeneity

by Dinara Baiskhanova, Maike Menzel, Claudia Geismann, Christoph Röcken, Eric Beitz, Susanne Sebens, Anna Trauzold and Heiner Schäfer

Int. J. Mol. Sci. 2025, 26(11), 5398; https://doi.org/10.3390/ijms26115398 - 4 Jun 2025

Viewed by 585

Abstract

Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells running the reverse Warburg metabolism. Key drivers of lactate transport are the carrier proteins SLC16A1 (import/export) and SLC16A3 (export). Expression and function of both carriers are controlled by the chaperone Basigin (BSG), which itself is functionally controlled by the transmembrane protease serine 11B (TMPRSS11B). In this study we explored the impact of TMPRSS11B on the phenotype of PDAC cells under reverse Warburg conditions. Amongst a panel of PDAC cell lines, Panc1 and BxPc3 cells were identified to express TMPRSS11B at a high level, whilst other cell lines such as T3M4 did not. ShRNA-mediated TMPRSS11B knock-down in Panc1 and BxPc3 cells enhanced lactate import through SLC16A1, as shown by GFP/iLACCO1 lactate uptake assay, whereas TMPRSS1B overexpression in T3M4 dampened SLC16A1-driven lactate uptake. Moreover, knock-down and overexpression of TMPRSS11B differentially impacted proliferation and chemoresistance under reverse Warburg conditions in Panc1 or BxPc3 and T3M4 cells, respectively, as well as their stemness properties indicated by altered colony formation rates and expression of the stem cell markers Nanog, Sox2, KLF4 and Oct4. These effects of TMPRSS11B depended on both SLC16A1 and BSG as shown by gene silencing. Immunohistochemical analysis revealed a reciprocal expression of TMPRSS11B and BSG together with SLC16A1 in some areas of tumor tissues from PDAC patients. Those regions exhibiting low or no TMPRSS11B expression but concomitant high expression of SLC16A1 and BSG revealed greater amounts of KLF4. In contrast, other tumor areas exhibiting high expression of TMPRSS11B together with BSG and SLC16A1 were largely negative for KLF4 expression. Thus, the differential expression of TMPRSS11B adds to metabolic heterogeneity in PDAC and its absence supports the reverse Warburg metabolism in PDAC cells by the enhancement of BSG-supported lactate uptake through SLC16A1 and subsequent phenotype alterations towards greater stemness. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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12 pages, 1028 KiB

Open AccessArticle

Plasma and Urine Circulating Tumor DNA Methylation Profiles for Non-Invasive Pancreatic Ductal Adenocarcinoma Detection: Significant Findings in Plasma Only

by Tomoaki Ito, Takumi Iwasawa, Shunsuke Sakuraba and Kenichiro Tanaka

Int. J. Mol. Sci. 2025, 26(11), 4972; https://doi.org/10.3390/ijms26114972 - 22 May 2025

Viewed by 666

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with limited treatment options, and early detection remains challenging due to the lack of reliable non-invasive biomarkers. This study investigated plasma and urine circulating tumor deoxyribonucleic acid (ctDNA) methylation profiles as potential biomarkers for PDAC detection. A total of 35 patients with PDAC and 10 non-cancerous controls were enrolled, and whole-genome bisulfite sequencing was performed on ctDNA extracted from both plasma and urine samples. Plasma ctDNA methylation profiles effectively distinguished cancerous from non-cancerous samples, particularly through differential methylation in intergenic regions. Hierarchical clustering further enabled the accurate grouping of patients with PDAC. However, urine ctDNA did not show significant methylation differences. These findings suggest that plasma ctDNA methylation holds promise as a non-invasive biomarker for PDAC detection, whereas urine ctDNA appears less informative. Future research should validate these findings in larger cohorts and investigate machine learning approaches to improve diagnostic performance, ultimately facilitating earlier detection and improved patient outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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25 pages, 13373 KiB

Open AccessArticle

Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201

by Tamás Czuczi, József Murányi, István Móra, Bianka Gurbi, Attila Varga, Dávid Papp, Gitta Schlosser, Miklós Csala and Antal Csámpai

Int. J. Mol. Sci. 2024, 25(23), 13176; https://doi.org/10.3390/ijms252313176 - 7 Dec 2024

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Abstract

Our ongoing research focuses on the development of new imipridone derivatives. We aim to design compounds that can completely and selectively eradicate cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity against PANC-1 and Fadu cell lines. We have also conducted preliminary studies on the mechanism, including colony formation as well as dose–response tests in HEK293T wild-type (WT) and HEK293T CLPP^−/− cells. Following gradual structural fine-tuning based on high throughput screening, we identified two imipridone hybrids as the most potent derivatives. Their unique substitution pattern includes N-methylated propargylamine and ferrocenyl/phenyltriazole moieties on the benzyl groups attached to opposite sides of the imipridone core. We found that the compounds with IC₅₀ values similar to those of ONC201 completely eradicated cancer cells at about 4 μM, while ONC201 treatment at even higher concentrations left 30–50% of viable cells behind. Both compounds exerted equal activity in WT and CLPP^−/− HEK293T cells, indicating a ClpP-independent mechanism. Further development is needed to improve the tumor selectivity of the two potent imipridone derivatives. By preserving tumor cytotoxicity, we aim to generate new drug candidates that evade resistance and can be applied in a sufficiently broad therapeutic window. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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18 pages, 5163 KiB

Open AccessArticle

Effect of Sodium-Glucose Co-Transporter 2 Inhibitors Combined with Metformin on Pancreatic Cancer Cell Lines

by André Cristovão, Nelson Andrade, Fátima Martel and Cláudia Silva

Int. J. Mol. Sci. 2024, 25(18), 9932; https://doi.org/10.3390/ijms25189932 - 14 Sep 2024

Cited by 2 | Viewed by 1491

Abstract

Pancreatic cancer (PC) is the ninth-leading cause of cancer-related deaths worldwide. Diabetic patients have an increased risk and mortality rates for PC. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and metformin (Met) are widely used anti-diabetic medications. Both Met and SGLT2 inhibitors have anticancer properties in PC, but nothing is known concerning their combined effect. So, we investigated the in vitro effect of SGLT2 inhibitors combined with Met. Canagliflozin and dapagliflozin possessed cytotoxic, antiproliferative, and pro-apoptotic properties in the tested PC cell lines. In PANC-1 cells, the antimigratory and pro-apoptotic effects were enhanced when dapagliflozin was combined with Met, and G1 cell cycle arrest was enhanced when dapagliflozin or canagliflozin was combined with Met. In AsPC-1 cells, the cytotoxic effect and the G1 cell cycle arrest were enhanced when canagliflozin and dapagliflozin, respectively, were combined with Met. Only the cytotoxic effects of SGLT2 inhibitors, but not the combination treatments, involved PI3K and JNK-dependent pathways in AsPC-1 cells. In conclusion, combination treatments increased the anticancer effects in a cell type-dependent way in the two investigated cell lines. Additionally, the cytotoxic effect of SGLT2 inhibitors was dependent on the PI3K and JNK pathways in AsPC-1 cells, but Met appears to act via a distinct mechanism. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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14 pages, 621 KiB

Open AccessArticle

Mature MUC5AC Expression in Resected Pancreatic Ductal Adenocarcinoma Predicts Treatment Response and Outcomes

by Ashish Manne, Ashwini Esnakula, Ankur Sheel, Amir Sara, Upender Manne, Ravi Kumar Paluri, Kai He, Wancai Yang, Davendra Sohal, Anup Kasi, Anne M. Noonan, Arjun Mittra, John Hays, Sameek Roychowdhury, Pannaga Malalur, Shafia Rahman, Ning Jin, Jordan M. Cloyd, Susan Tsai, Aslam Ejaz, Kenneth Pitter, Eric Miller, Kannan Thanikachalam, Mary Dillhoff and Lianbo Yu Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(16), 9041; https://doi.org/10.3390/ijms25169041 - 20 Aug 2024

Cited by 2 | Viewed by 1759

Abstract

Neoadjuvant therapy (NAT) for early-stage pancreatic ductal adenocarcinoma (PDA) has recently gained prominence. We investigated the clinical significance of mucin 5 AC (MUC5AC), which exists in two major glycoforms, a less-glycosylated immature isoform (IM) and a heavily glycosylated mature isoform (MM), as a biomarker in resected PDA. Immunohistochemistry was performed on 100 resected PDAs to evaluate the expression of the IM and MM of MUC5AC using their respective monoclonal antibodies, CLH2 (NBP2-44455) and 45M1 (ab3649). MUC5AC localization (cytoplasmic, apical, and extra-cellular (EC)) was determined, and the H-scores were calculated. Univariate and multivariate (MVA) Cox regression models were used to estimate progression-free survival (PFS) and overall survival (OS). Of 100 resected PDA patients, 43 received NAT, and 57 were treatment-naïve with upfront surgery (UpS). In the study population (n = 100), IM expression (H-scores for objective response vs. no response vs. UpS = 104 vs. 152 vs. 163, p = 0.01) and MM-MUC5AC detection rates (56% vs. 63% vs. 82%, p = 0.02) were significantly different. In the NAT group, MM-MUC5AC-negative patients had significantly better PFS according to the MVA (Hazard Ratio: 0.2, 95% CI: 0.059–0.766, p = 0.01). Similar results were noted in a FOLFIRINOX sub-group (n = 36). We established an association of MUC5AC expression with treatment response and outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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Review

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36 pages, 2305 KiB

Open AccessReview

Dysbiosis–NK Cell Crosstalk in Pancreatic Cancer: Toward a Unified Biomarker Signature for Improved Clinical Outcomes

by Sara Fanijavadi and Lars Henrik Jensen

Int. J. Mol. Sci. 2025, 26(2), 730; https://doi.org/10.3390/ijms26020730 - 16 Jan 2025

Cited by 2 | Viewed by 1844

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME), which contributes to treatment resistance. Recent research shows that the microbiome, including microbial communities in the oral cavity, gut, bile duct, and intratumoral environments, plays a key role in PDAC development, with microbial imbalances (dysbiosis) promoting inflammation, cancer progression, therapy resistance, and treatment side effects. Microbial metabolites can also affect immune cells, especially natural killer (NK) cells, which are vital for tumor surveillance, therapy response and treatment-related side effects. Dysbiosis can affect NK cell function, leading to resistance and side effects. We propose that a combined biomarker approach, integrating microbiome composition and NK cell profiles, can help predict treatment resistance and side effects, enabling more personalized therapies. This review examines how dysbiosis contributes to NK cell dysfunction in PDAC and discusses strategies (e.g., antibiotics, probiotics, vaccines) to modulate the microbiome and enhance NK cell function. Targeting dysbiosis could modulate NK cell activity, improve the effectiveness of PDAC treatments, and reduce side effects. However, further research is needed to develop unified NK cell–microbiome interaction-based biomarkers for more precise and effective patient outcomes. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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38 pages, 3654 KiB

Open AccessReview

Targeting Triple NK Cell Suppression Mechanisms: A Comprehensive Review of Biomarkers in Pancreatic Cancer Therapy

by Sara Fanijavadi, Mads Thomassen and Lars Henrik Jensen

Int. J. Mol. Sci. 2025, 26(2), 515; https://doi.org/10.3390/ijms26020515 - 9 Jan 2025

Cited by 6 | Viewed by 2816

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes due to frequent recurrence, metastasis, and resistance to treatment. A major contributor to this resistance is the tumor’s ability to suppress natural killer (NK) cells, which are key players in the immune system’s fight against cancer. In PDAC, the tumor microenvironment (TME) creates conditions that impair NK cell function, including reduced proliferation, weakened cytotoxicity, and limited tumor infiltration. This review examines how interactions between tumor-derived factors, NK cells, and the TME contribute to tumor progression and treatment resistance. To address these challenges, we propose a new “Triple NK Cell Biomarker Approach”. This strategy focuses on identifying biomarkers from three critical areas: tumor characteristics, TME factors, and NK cell suppression mechanisms. This approach could guide personalized treatments to enhance NK cell activity. Additionally, we highlight the potential of combining NK cell-based therapies with conventional treatments and repurposed drugs to improve outcomes for PDAC patients. While progress has been made, more research is needed to better understand NK cell dysfunction and develop effective therapies to overcome these barriers. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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