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Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition
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Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition

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 8456

Special Issue Editor

Dr. Donatella Delle Cave

E-Mail Website
Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pancreatic cancer
  • metabolism
  • cellular plasticity
  • tumor microenvironment
  • target therapy

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Related Special Issue

Published Papers (6 papers)

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Research

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12 pages, 1028 KiB  
Article
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
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 [...] Read more.
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  
Article
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
Viewed by 1034
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 [...] Read more.
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  
Article
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 1301
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 [...] Read more.
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  
Article
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 Yuadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(16), 9041; https://doi.org/10.3390/ijms25169041 - 20 Aug 2024
Cited by 1 | Viewed by 1600
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 [...] Read more.
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  
Review
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 1 | Viewed by 1520
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, [...] Read more.
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  
Review
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 2 | Viewed by 2142
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 [...] Read more.
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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