Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

TLDR

Pancreatic stellate cells become cancer‑associated fibroblasts that secrete desmoplastic stroma, influencing progression and treatment response in pancreatic ductal adenocarcinoma. The study aimed to determine whether CAFs in PDA are functionally homogeneous or comprise distinct phenotypic subpopulations. They discovered two CAF subsets: an α‑smooth muscle actin–rich population adjacent to tumor cells that produces desmoplastic stroma, and a more distant IL‑6–secreting inflammatory subset, confirming CAF heterogeneity in PDA and suggesting new therapeutic targets.

Abstract

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). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. 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. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. 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. 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.