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. (March 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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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:	Olund, Daniel Handly-Santana, Abram Biffi, Giulia Elyada, Ela Santos De Almeida, Ana Margarida Ponz Sarvise, Mariano Corbo, Vincenzo Oni, Tobiloba Hearn, Stephen A. Chio, Iok In Hwang, Chang-Il Tiriac, Herve Baker, Lindsey Engle, Dannielle Egeblad, Mikala Fearon, Douglas Park, Youngkyu Tuveson, David A. Lee, Eunjung
Communities:	CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Egeblad lab CSHL labs > Fearon lab CSHL labs > Tuveson lab CSHL Cancer Center Program > Signal Transduction
Depositing User:	Matt Covey
Date:	6 March 2017
Date Deposited:	02 Mar 2017 15:57
Last Modified:	05 Mar 2018 19:51
PMCID:	PMC5339682
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/34140

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