Unveiling chemoresistance in pancreatic cancer: the role of AD-MSC, key resistance genes, and TCDCA-driven molecular insights

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This thesis investigates the complex interactions within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), focusing on the roles of bile acids, stromal cells, and chemotherapeutic agents in tumor progression and chemoresistance. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, characterized by late-stage diagnosis and limited treatment options. This study provides a comprehensive examination of the potential interplay between adipose-derived stromal cells (AD-MSCs), bile acids, and chemotherapeutic agents in tumorigenesis and chemotherapy response within PDAC. I. Bile Acids and PDAC Progression Bile acids, especially TCDCA, play a significant role in gastrointestinal cancers, including PDAC. Their impact depends on factors like hydrophobicity, transport mechanisms, and organ-specific signaling pathways. Elevated serum BA levels, often linked to obstructive jaundice (OJ), correlate with worse survival outcomes in PDAC patients. BAs influence gene expression through the FXR/NF-κB pathway, enhancing markers like CDX2 and MUC2, which are associated with tumorigenesis. Using RNA sequencing on Capan- 1 PDAC cells, our study uncovered 2,950 differentially expressed genes (DEGs) following 24- hour TCDCA treatment. Among the upregulated genes, DKK-1, SerpinB2, KRT80, FST, FGFBP1, and UPLA were identified as significant contributors to PDAC tumorigenesis, metastasis, and cell migration. For example, DKK-1 emerged as a promising diagnostic and prognostic biomarker for PDAC due to its strong association with disease progression and poor prognosis. Similarly, elevated KRT80 expression is linked to increased proliferation and invasiveness. UPLA and SerpinB2, involved in extracellular matrix (ECM) remodelling, further underscore the role of BAs in enhancing PDAC progression. These findings suggest that targeting BA-driven pathways could provide novel therapeutic strategies. II. Stromal Cells and Chemoresistance Adipose-derived mesenchymal stromal cells (ADMSCs) are pivotal components of the tumor microenvironment (TME), contributing to cancer drug resistance through their tumor-homing abilities and secretory profiles. This study explored the effects of oxaliplatin (OXP), 5-fluorouracil (5-FU) and gemcitabine (GEM) on AD-MSCs and Capan-1 cells. MTT assays revealed that while Capan-1 cells exhibited dose-dependent viability reductions, AD-MSCs demonstrated remarkable resistance, maintaining over 90% viability even at cytotoxic drug concentrations. This resistance likely stems from AD-MSCs’ efficient DNA repair mechanisms and low proliferative rates. 55 Transcriptomic and Cytokine Profiling RNA sequencing showed that OXP induced significant transcriptional changes in AD-MSCs, with over 7,000 DEGs, while 5-FU caused minimal impact. Key pathways affected by OXP included DNA damage response, p53- mediated cell cycle arrest, and cytokine signaling. GO enrichment analysis highlighted the activation of immune-modulatory pathways, including IL6/JAK/STAT3 and hypoxia signaling, which contribute to chemoresistance. In contrast, 5-FU’s limited effects on AD-MSCs suggest its selective cytotoxicity against cancer cells. Protein array analysis revealed that OXP-treated AD-MSCs altered their secretome to foster a pro-tumoral environment, reducing proangiogenic factors like VEGF while increasing stress-related proteins and ECM modulators. Notably, cytokines such as GROα and IL-4 were upregulated under OXP, promoting immune suppression and ECM remodelling. Conversely, 5-FU-treated AD-MSCs showed reduced metastatic potential, with lower expression of ECM remodelling factors and chemokines like SDF-1α. These results emphasize the differential impact of these drugs on stromal cell behavior and their potential to shape the TME. Therapeutic strategies targeting AD-MSC-secreted factors such as GROα, GM-CSF, EMMPRIN, and IL-4 and pathways involved in hypoxia signaling, immune modulation, and ECM remodelling could mitigate the supportive role of AD-MSCs and enhance treatment efficacy. Future research should leverage multi-omics approaches to dissect the precise roles of AD-MSC-derived factors in tumor progression and resistance, aiming to develop innovative strategies that disrupt stromal-tumor crosstalk. This approach holds promise for overcoming resistance and improving outcomes in PDAC and other stromal-rich cancers. Collectively, these findings deepen our understanding of the molecular mechanisms driving AD-MSC-mediated chemotherapy resistance and bile acid-induced tumor promotion, paving the way for targeted therapies to improve patient outcomes. III. 3D model of pancreatic cancer We explored 3D bioprinting as a method for developing a 3D model of pancreatic cancer and artificial pancreatic islets.

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