Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Daniel Öhlund, 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, Hervé Tiriac, Lindsey A Baker, Dannielle D Engle, Christine Feig, Anne Kultti, Mikala Egeblad, Douglas T Fearon, James M CrawfordHans Clevers, Youngkyu Park, David A Tuveson

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)579-596
Number of pages18
JournalJournal of Experimental Medicine
Volume214
Issue number3
DOIs
Publication statusPublished - 06 Mar 2017

Keywords

  • Actins
  • Animals
  • Carcinoma, Pancreatic Ductal
  • Cells, Cultured
  • Cytokines
  • Fibroblasts
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts
  • Pancreatic Neoplasms
  • STAT3 Transcription Factor
  • Journal Article

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