Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer.

Daniel Öhlund,Vincenzo Corbo,Chang-Il Hwang,Ana S Almeida,James M Crawford,Ela Elyada,Anne Kultti,Eun Jung Lee,Mikala Egeblad,Giulia Biffi,Hans Clevers,Douglas T Fearon,Tobiloba E Oni,Christine Feig,Hervé Tiriac,David A Tuveson,Abram Handly-Santana,Iok In Christine Chio,Lindsey A Baker,Dannielle D Engle,Young-Kyu Park ,Mariano Ponz-Sarvisé ,Stephen Hearn

doi:10.1084/jem.20162024

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.

Highlights

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
Heterogeneous distribution of myofibroblastic cancer-associated fibroblast (CAF) in PDA To investigate the inherent heterogeneity of fibroblasts in pancreatic cancer, we evaluated the spatial distribution of α-smooth muscle actin (αSMA), a hallmark of myofibroblasts (Desmoulière et al, 2004), in human pancreatic tumors
These fibroblast-activation protein α (FAP)+ αSMAhigh cells could be delineated by RNA in situ hybridization (ISH), and were located in direct proximity to neoplastic cells, forming a periglandular ring surrounding cancer cell clusters (Fig. 1 B).A gradient of αSMA expression was observed in tumors from KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-1-Cre) mice (Fig. 1, C and D), a mouse model that recapitulates the human disease (Hingorani et al, 2005)