Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund D (1,2,3), Handly-Santana A (1,2), Biffi G (1,2), Elyada E (1,2), Almeida AS (1,4), Ponz-Sarvise M (1,2,5), Corbo V (1,2,6,7), Oni TE (1,2,8), Hearn SA( 1), Lee EJ (1,2), Chio II (1,2), Hwang CI (1,2), Tiriac H (1,2), Baker LA (1,2), Engle DD (1,2), Feig C (9), Kultti A (9), Egeblad M (1), Fearon DT (1), Crawford JM (10), Clevers H (11), Park Y (1,2), Tuveson DA (1,2).
(1) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
(2) Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724.
(3) Department of Surgical and Perioperative Sciences, Surgery, Umeå University, 901 85 Umeå, Sweden.
(4) APC Microbiome Institute and School of Microbiology, University College Cork, Cork, Ireland.
(5) Department of Oncology, Clinica Universidad de Navarra, CIMA, IDISNA, Pamplona 31008, Spain.
(6) ARC-Net centre for applied research on cancer, University and Hospital Trust of Verona, 37134 Verona, Italy.
(7) Department of Diagnostic and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy.
(8) Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794.
(9) University of Cambridge, Cancer Research UK, Cambridge Institute, Cambridge, UK.
(10) Hofstra Northwell School of Medicine, Hempstead, NY 11550.
(11) Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584 CT Utrecht, Netherlands.
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.
CITATION J Exp Med. 2017 Mar 6;214(3):579-596. doi: 10.1084/jem.20162024. Epub 2017 Feb 23