![]() ![]() ![]() CAFs secrete ECM and soluble factors that stimulate cancer progression, and are believed to be derived from mesenchymal cells of different origins that are resident or recruited to the pancreas by neoplastic cells ( Öhlund et al., 2014 Moffitt et al., 2015 Kalluri, 2016). PDA is characterized by abundant desmoplasia that constitutes up to 90% of the total tumor volume and contains extracellular matrix (ECM), immune cells, vasculature, and cancer-associated fibroblasts (CAFs Moir et al., 2015). Indeed, the current systemic therapies for patients with advanced PDA provide only temporary benefits, highlighting the need for new therapeutic strategies. Patients are often diagnosed late during disease progression, when curative surgical approaches are not feasible. ![]() Pancreatic ductal adenocarcinoma (PDA) has one of the worst outcomes among all cancers, with a median survival of ∼6 mo and a 5-yr survival rate of <8% ( Siegel et al., 2016). These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). ![]()
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