Human Pancreatic Cancer Associated Fibroblasts

Pancreatic cancer-associated fibroblasts (CAFs) exhibit remarkable phenotypic and functional heterogeneity. Single-cell transcriptomic analyses have identified at least three major CAF subtypes in PDAC: myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs). More recent integrated analyses have further refined this landscape, revealing nine distinct CAF subtypes including transitional CAFs (tCAFs), proliferative CAFs (pCAFs), and CDCP1⁺FTL⁺ CAFs. These subtypes exhibit differentiation plasticity, transitioning from early normal-like CAFs to iCAFs and myCAFs, ultimately giving rise to more invasive pCAFs.

The functional significance of pancreatic CAFs extends across multiple pro-tumorigenic axes: remodeling the extracellular matrix, secreting growth factors and cytokines such as TGF-β and IL-6, promoting angiogenesis, and establishing an immunosuppressive niche. Notably, CAFs can either promote or suppress tumor progression in a context-dependent manner. Specific subtypes, including ECM-remodeling myCAFs, hypoxic CAFs, and iCAF_chemokine subpopulations, have been associated with immune-excluded, chemoresistant phenotypes and poor clinical outcomes. Furthermore, CDCP1⁺FTL⁺ CAFs exhibit enhanced glycolysis and iron metabolism, resisting ferroptosis.

Human pancreatic CAFs are invaluable as a physiologically relevant in vitro model system. These cells are extensively employed in co-culture systems with PDAC cell lines and patient-derived organoids to recapitulate tumor-stroma interactions, study CAF-mediated chemoresistance, and evaluate novel therapeutic interventions. CAF-related gene signatures have demonstrated robust prognostic value, effectively stratifying patient survival and predicting treatment response. Collectively, human pancreatic CAFs are indispensable for dissecting PDAC pathogenesis and advancing precision oncology, serving as both a powerful experimental platform and a compelling therapeutic target.