Distinct Populations of Inflammatory Fibroblasts and Myofibroblasts in Pancreatic Cancer

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2017 Feb 25

PMID 28232471

Citations 1225

Authors

Daniel Ohlund

Abram Handly-Santana

Giulia Biffi

Ela Elyada

Ana S Almeida

Mariano Ponz-Sarvise

Vincenzo Corbo

Tobiloba E Oni

Stephen A Hearn

Eun Jung Lee

Iok In Christine Chio

Chang-Il Hwang

Herve Tiriac

Lindsey A Baker

Dannielle D Engle

Christine Feig

Anne Kultti

Mikala Egeblad

Douglas T Fearon

James M Crawford

Hans Clevers

Youngkyu Park

David A Tuveson

Affiliations

Soon will be listed here.

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.

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