Gene expression dynamics in fibroblasts during early-stage murine pancreatic carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal malignancies, characterized by aggressive local tumor growth and metastatic spread, in part driven by fibroblast-mediated stromal reactions in the tumor microenvironment. Early detection is critical for improved patient outcomes. In this study, we investigate the molecular cues within fibroblasts that offer promise for early PDAC diagnosis. We employ RNA sequencing of fibroblasts from KPC mouse models at pivotal time points, corresponding to the early preinvasive stages of pancreatic cancer. Our analysis reveals a substantial upregulation of gene sets associated with adipogenesis, fatty acid metabolism, and the ROS pathway in 12-week KPC-fibroblasts, indicative of metabolic reprogramming and redox regulation during early PDAC initiation. We narrow our focus to 26 potential key genes that may facilitate paracrine communication between fibroblasts and preneoplastic cells. Validation of our findings confirms the consistent increase in Angptl4, a gene linked to adipogenesis, and the notable downregulation of Lama2, a crucial extracellular matrix (ECM) gene. This study is the first to observe the elevation of Angptl4 in KPC-fibroblasts, providing essential insights into the role of fibroblasts in early PDAC. Moreover, our results hint at a potential role of fibroblasts in ECM degradation, a process that could support cancer cell proliferation and metastatic invasion. Genes associated with the ECM consistently display downregulation. These discoveries lay the foundation for future investigations into the mechanisms driving fibroblast-mediated elevation of Angptl4 and downregulation of ECM genes and their role in mediating crosstalk between fibroblast and preneoplastic cells. Our investigation into fibroblast transcriptional dynamics during early carcinogenesis offers significant potential for enhancing early diagnostic approaches in combating this deadly malignancy.