Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 23, 2017
- Source ID
- 10.1084/jem.20162024
Entities
People
- Abram Handly-santana
- Ana S Almeida
- Anne Kultti
- Chang-il Hwang
- Christine Feig
- Daniel Öhlund
- Dannielle D Engle
- David Tuveson
- Douglas T Fearon
- Ela Elyada
- Eun Jung Lee
- Giulia Biffi
- Hans Clevers
- Hervé Tiriac
- Iok In Christine Chio
- James M. Crawford
- Lindsey Baker
- Mariano Ponz-sarvise
- Mikala Egeblad
- Stephen A Hearn
- Tobiloba E Oni
- Vincenzo Corbo
- Youngkyu Park
Organizations
- Cancer Research Foundation in Northern Sweden
- Clínica Universidad de Navarra
- Cold Spring Harbor Laboratory
- Damon Runyon Cancer Research Foundation
- European Molecular Biology Organization
- Hofstra University
- Kempe Foundation
- Lustgarten Foundation for Pancreatic Cancer Research
- Ministry of Health of Italy
- National Cancer Institute
- National Institutes of Health
- Stand Up to Cancer
- Stony Brook University
- Swedish Research Council
- Swedish Society of Medicine
- The Starr Foundation
- Umeå University
- United States Department of Defense
- University College Cork
- University Medical Center Utrecht
- University of Cambridge
- Weizmann Institute of Science