This study investigates the heterogeneity of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDA). The authors identified a subpopulation of CAFs with elevated expression of α-smooth muscle actin (αSMA) located near neoplastic cells in both mouse and human PDA tissues. They demonstrated that these αSMAhigh CAFs produce desmoplastic stroma through co-cultures of pancreatic stellate cells (PSCs) and organoids. Additionally, they discovered another distinct subpopulation of CAFs, which lack elevated αSMA expression but secrete inflammatory cytokines like IL6. These findings were validated in mouse and human PDA tissues, highlighting the existence of two spatially separated and mutually exclusive CAF subtypes. The study also reveals that the inflammatory CAFs (iCAFs) are induced by paracrine signaling from cancer cells and are located more distantly from neoplastic cells, while the myofibroblastic CAFs (myCAFs) form in close proximity to cancer cells. The results suggest that targeting specific CAF populations may be a promising approach for developing effective therapies in PDA.This study investigates the heterogeneity of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDA). The authors identified a subpopulation of CAFs with elevated expression of α-smooth muscle actin (αSMA) located near neoplastic cells in both mouse and human PDA tissues. They demonstrated that these αSMAhigh CAFs produce desmoplastic stroma through co-cultures of pancreatic stellate cells (PSCs) and organoids. Additionally, they discovered another distinct subpopulation of CAFs, which lack elevated αSMA expression but secrete inflammatory cytokines like IL6. These findings were validated in mouse and human PDA tissues, highlighting the existence of two spatially separated and mutually exclusive CAF subtypes. The study also reveals that the inflammatory CAFs (iCAFs) are induced by paracrine signaling from cancer cells and are located more distantly from neoplastic cells, while the myofibroblastic CAFs (myCAFs) form in close proximity to cancer cells. The results suggest that targeting specific CAF populations may be a promising approach for developing effective therapies in PDA.