Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Ohlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., Chio, II, Hwang, C. I., Tiriac, H., Baker, L. A., Engle, D. D., Feig, C., Kultti, A., Egeblad, M., Fearon, D. T., Crawford, J. M., Clevers, H., Park, Y., Tuveson, D. A. (2017) Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med, 214 (3). pp. 579-596. ISSN 0022-1007

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URL: https://www.ncbi.nlm.nih.gov/pubmed/28232471
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 alpha-smooth muscle actin (alphaSMA) 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 alphaSMA 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.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts

diseases & disorders > inflammation
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > Microscopy Service
CSHL labs > Egeblad lab
CSHL labs > Fearon lab
CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 02 Mar 2017 15:57
Last Modified: 06 Nov 2017 20:15
PMCID: PMC5339682
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34140

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