Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

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Öhlund, Daniel
Handly-Santana, Abram
Biffi, Giulia
Elyada, Ela
Almeida, Ana S.
Ponz-Sarvise, Mariano
Corbo, Vincenzo
Oni, Tobiloba E.
Hearn, Stephen A.
Lee, Eun Jung
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Rockefeller University Press
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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 a-smooth muscle actin (alpha SMA) 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 aSMA 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.
Stellate cells , Ductal adenocarcinoma , Tumor microenvironment , RNA-seq , Stroma , Progression , Interleukin-6 , Gemcitabine , Resistance , Differentiation
Öhlund, 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, I. I. C., 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. and Tuveson, D. A. (2017) 'Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer', Journal of Experimental Medicine, 214(3), pp. 579-596. doi: 10.1084/jem.20162024