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Deciphering Molecular Complexity of Pancreatic Cancer

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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: 20 June 2026 | Viewed by 10053

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Special Issue Editor

Prof. Dr. Dimitrios H. Roukos

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Guest Editor

Centre for Biosystems and Genome Network Medicine, Ioannina University, Ioannina, Greece
Interests: precision cancer medicine; precision immuno-oncoloy; precision oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic cancer, known for its insidious onset, aggressive nature and poor prognosis, remains one of the most challenging malignancies to diagnose and treat. With a 5-year survival rate of 12%, which has remained at this level for the past few years, pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer death in the United States and is projected to become the second leading cause of cancer-related deaths within this decade. Even in patients treated with curative intent, recurrence rates remain very high (80-90%) despite surgical resection with standard neoadjuvant and/or adjuvant chemotherapy. Minimal residual disease (MRD) and resistance to chemotherapy represent the main causes of treatment failure. At the heart of its elusive nature lies its staggering molecular complexity that underpins its diverse pathogenesis, heterogeneity, and resistance to therapeutic interventions. This Special Issue aims to delve into the intricate molecular landscape of pancreatic cancer, unraveling its complexities and exploring promising avenues for overcoming the clinical hurdles associated with this devastating disease.

Moreover, this Special Issue highlights emerging strategies and potential solutions to dissect the dynamics of intratumor components and complex interactions between the cancer cells and immune cells of the tumor microenvironment (TME) by integrating innovative high-precision multiomics technologies. From precision medicine approaches targeting specific genetic alterations and immunotherapy harnessing the power of the immune system to novel drug delivery systems designed to overcome tumor heterogeneity, plasticity, early micrometastasis and resistance to current standard therapy, we showcase the latest advances in this field. We also examine the role of basic research in advancing our understanding of pancreatic cancer biology and how these insights can inform the development of more effective and tailored therapies. We welcome contributions that span the breadth of pancreatic cancer research, fostering interdisciplinary collaborations and stimulating models to translate novel ideas into decision-making processes for early diagnosis and multimodal treatment; this is possible via the development of novel frameworks of tumor and liquid biopsy-based biomarkers to guide meaningful therapy, including next-generation immune checkpoint inhibitors and mRNA vaccines.

Prof. Dr. Dimitrios H. Roukos
Guest Editor

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Keywords

pancreatic cancer
intratumor heterogeneity
bulk and single-cell multiomics
tumor microenvironment
cancer immunotherapy
targeted therapy

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Published Papers (5 papers)

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Research

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24 pages, 2077 KB

Open AccessArticle

Deciphering RTK-RAS and MAPK Pathway Dependencies in Gemcitabine-Treated Pancreatic Ductal Adenocarcinoma Through Conversational Artificial Intelligence

by Fernando C. Diaz, Brigette Waldrup, Francisco G. Carranza, Sophia Manjarrez and Enrique Velazquez-Villarreal

Int. J. Mol. Sci. 2026, 27(7), 3011; https://doi.org/10.3390/ijms27073011 - 26 Mar 2026

Viewed by 248

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy marked by substantial molecular heterogeneity and variable response to gemcitabine-based therapy. While KRAS mutations are nearly universal, the broader RTK-RAS and MAPK signaling architecture and its relationship to treatment response remain incompletely defined. We conducted an integrative clinical-genomic analysis of 184 PDAC tumors stratified by age at diagnosis and gemcitabine exposure, interrogating somatic alterations across curated RTK-RAS/MAPK gene sets. Conversational artificial intelligence agents (AI-HOPE-RTK-RAS and AI-HOPE-MAPK) enabled dynamic cohort construction and pathway-level analyses, with findings validated using standard statistical methods. In late-onset PDAC, ERBB2 and RET mutations were significantly enriched in gemcitabine-treated tumors. Early-onset cases demonstrated differential enrichment of CACNA2D family alterations in non-treated tumors and higher frequencies of FLNB and TP53 mutations in treated disease. Importantly, late-onset patients not treated with gemcitabine who lacked RTK-RAS or MAPK alterations exhibited significantly improved overall survival. These findings reveal age- and treatment-dependent pathway dependencies beyond canonical KRAS status and support a precision oncology framework in PDAC. Conversational AI facilitated rapid, multidimensional clinical–genomic integration to uncover clinically relevant signaling substructures. Full article

(This article belongs to the Special Issue Deciphering Molecular Complexity of Pancreatic Cancer)

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23 pages, 1519 KB

Open AccessArticle

Comparative Tumor Microenvironment Analysis for HCC and PDAC Using KMplotter

by Wen-Han Chang, Drashya Shah, Scott Myers, Michael Potts, Sanjive Qazi and Vuong Trieu

Int. J. Mol. Sci. 2025, 26(24), 11920; https://doi.org/10.3390/ijms262411920 - 10 Dec 2025

Viewed by 778

Abstract

Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are highly lethal cancers marked by profound epigenetic and metabolic reprogramming. Among the candidate biomarkers, the DNA methyltransferase DNMT3A and the guanine monophosphate synthetase (GMPS) have emerged as potential prognostic drivers, yet their roles across tumor contexts remain unclear. Here, we demonstrate the application of KMplotter to interrogated pan-cancer transcriptomic and survival datasets encompassing over 7000 patients, complemented by expression profiling of normal, tumor, and metastatic tissues, and integrated tumor microenvironment (TME) analyses. Elevated DNMT3A and GMPS expression correlated with worse overall survival in HCC, particularly in Asian patients, while in PDAC, high DNMT3A but low GMPS expression predicted favorable outcomes. Both genes were consistently upregulated in tumors relative to normal tissues, with further increases in metastatic HCC. Immune deconvolution revealed that DNMT3A was linked to Th2/Treg-enriched niches, whereas GMPS overexpression coincided with high mutational burden or stromal enrichment, fostering immunosuppressive microenvironments. Comparative analysis of toll-like receptor signatures highlighted divergent antigen-sensing pathways, with HCC reflecting viral-driven immune exhaustion and PDAC showing self-antigen–associated signaling. Collectively, these findings position DNMT3A and GMPS as context-dependent biomarkers that integrate metabolic and immune cues to shape prognosis in liver and pancreatic cancer, offering mechanistic insight and translational relevance for patient stratification. Full article

(This article belongs to the Special Issue Deciphering Molecular Complexity of Pancreatic Cancer)

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38 pages, 6041 KB

Open AccessArticle

Deciphering of SOX9 Functions in Pancreatic Cancer Cells

by Kirill Kashkin, Liya Kondratyeva, Eugene Kopantzev, Ivan Abramov, Lyudmila Zhukova and Igor Chernov

Int. J. Mol. Sci. 2025, 26(6), 2652; https://doi.org/10.3390/ijms26062652 - 15 Mar 2025

Cited by 1 | Viewed by 3108

Abstract

SOX9 is widely regarded as a key master regulator of gene transcription, responsible for the development and differentiation programs within tissue and organogenesis, particularly in the pancreas. SOX9 overexpression has been observed in multiple tumor types, including pancreatic cancer, and is discussed as a prognostic marker. In order to gain a more profound understanding of the role of SOX9 in pancreatic cancer, we have performed SOX9 knockdown in the COLO357 and PANC-1 cells using RNA interference, followed by full-transcriptome analysis of the siRNA-transfected cells. The molecular pathway enrichment analysis between SOX9-specific siRNA-transfected cells and control cells reveals the activation of processes associated with cellular signaling, cell differentiation, transcription, and methylation, alongside the suppression of genes involved in various stages of the cell cycle and apoptosis, upon the SOX9 knockdown. Alterations of the expression of transcription factors, epithelial–mesenchymal transition markers, oncogenes, tumor suppressor genes, and drug resistance-related genes upon SOX9 knockdown in comparison of primary and metastatic pancreatic cancer cells are discovered. The expression levels of genes comprising prognostic signatures for pancreatic cancer were also evaluated following SOX9 knockdown. Additional studies are needed to assess the properties and prognostic significance of SOX9 in pancreatic cancer using other biological models. Full article

(This article belongs to the Special Issue Deciphering Molecular Complexity of Pancreatic Cancer)

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15 pages, 2042 KB

Open AccessArticle

Low Bacterial Biomass in Human Pancreatic Cancer and Adjacent Normal Tissue

by Michael S. May, Heekuk Park, Dalia H. Moallem, Dwayne Seeram, Sun Dajiang, Hanina Hibshoosh, Jacob K. Jamison, Anne-Catrin Uhlemann and Gulam A. Manji

Int. J. Mol. Sci. 2025, 26(1), 140; https://doi.org/10.3390/ijms26010140 - 27 Dec 2024

Cited by 7 | Viewed by 2496

Abstract

The gut microbiome plays an important role in the carcinogenesis of luminal gastrointestinal malignancies and response to antineoplastic therapy. Preclinical studies have suggested a role of intratumoral gammaproteobacteria in mediating response to gemcitabine-based chemotherapy in pancreatic ductal adenocarcinoma (PDAC). To our knowledge, this is the first study to evaluate the impact of the PDAC microbiome on chemotherapy response using samples from human pancreatic tumor resections. We performed 16S rRNA gene amplification and sequencing on both formalin-fixed paraffin-embedded (FFPE) and fresh frozen human PDAC resection samples. We analyzed frozen samples from 26 patients with resected PDAC and examined tumor and tumor-adjacent normal tissue. These patients represented nine long-term survivors (LTS) and nine short-term survivors (STS) after neoadjuvant gemcitabine therapy and eight control patients who did not receive any neoadjuvant therapy prior to resection. We also included FFPE samples from five patients, including tumor samples (3 samples per patient), tumor-adjacent normal tissue (2 per patient) and tumor-adjacent paraffin (1 per patient). Within frozen tissue, total DNA yields were high, but bacterial DNA was generally low, comparable to those seen in negative controls. In FFPE tissue, DNA yields were low and bacterial abundances were comparable in paraffin, tumor and normal PDAC samples. Gammaproteobacteria concentrations did not correlate with outcomes in patients treated with neoadjuvant gemcitabine-based chemotherapy. Our study found low microbial biomass in pancreatic tumor tissue, with no detectable association between bacterial taxa and chemotherapy outcomes. These results suggest a limited role of the microbiome in gemcitabine-based chemotherapy response in PDAC. Preclinical studies have implicated the pancreatic tumor microbiome in driving response to therapy. Cytidine deaminase, an enzyme produced by gammaproteobacteria, can metabolize gemcitabine and has been hypothesized to inhibit pancreatic tumor response to chemotherapy. Several clinical trials have evaluated the role of the tumor microbiome in pancreatic cancer treatment. We evaluated the impact of the pancreatic tumor microbiome on chemotherapy response using samples from human pancreatic tumor resections. We found a low microbial load that is partially attributable to contaminants and that gammaproteobacteria levels did not correlate with outcomes in patients with pancreatic cancer treated with gemcitabine-based chemotherapy. Full article

(This article belongs to the Special Issue Deciphering Molecular Complexity of Pancreatic Cancer)

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Review

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32 pages, 2473 KB

Open AccessReview

DNA Damage and Repair in Pancreatic Cancer—The Latest Findings

by Małgorzata Kozłowska, Michał Mik, Michał Nowicki and Agnieszka Śliwińska

Int. J. Mol. Sci. 2025, 26(20), 10106; https://doi.org/10.3390/ijms262010106 - 17 Oct 2025

Cited by 1 | Viewed by 2589

Abstract

Pancreatic cancer is one of the most common cancers of the gastrointestinal tract, alongside stomach and colon cancers, yet remains among the least studied. Due to its non-specific symptoms, late diagnosis, and limited treatment options, it is associated with a poor prognosis and high mortality. Major risk factors for pancreatic cancer include smoking, alcohol consumption, pancreatitis, obesity, and type 2 diabetes. These environmental factors can damage DNA through various mechanisms and, if not properly repaired, may initiate carcinogenesis. DNA repair is one of the key mechanisms in cancer prevention. It has been suggested that impaired DNA repair may contribute to the development and progression of pancreatic cancer. The aim of this review is to highlight the link between environmental factors, DNA damage and DNA repair in pancreatic cancer. Environmental exposures can trigger a cascade of molecular events, including ROS (reactive oxygen species) overproduction, oxidative stress, insulin resistance, hyperglycemia, and inflammation, that lead to DNA damage. Additionally, up to 25% of patients with PDAC (pancreatic ductal adenocarcinoma) carry mutations in DDR (DNA damage response) genes, and only 5% of all cases are hereditary. Therefore, increased DNA damage combined with disturbances in DDR creates a condition accelerating pancreatic cancer progression. Further research should focus on DDR pathways as potential targets for screening and therapy. Such an approach could significantly improve early diagnosis and treatment outcomes. Moreover, uncovering the mechanisms linking pancreatic cancer aggressiveness with DNA repair deficiencies may lead to the development of specific biomarkers, enabling early detection and potentially improving patient survival. Full article

(This article belongs to the Special Issue Deciphering Molecular Complexity of Pancreatic Cancer)

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