Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

Journal of Experimental Medicine - Tập 214 Số 3 - Trang 579-596 - 2017
Daniel Öhlund1,2,3, Abram Handly-Santana2,3, Giulia Biffi2,3, Ela Elyada2,3, Ana S. Almeida4,5, Mariano Ponz‐Sarvisé6,2,3, Vincenzo Corbo7,8,2,3, Tobiloba E. Oni9,2,3, Stephen Hearn5, Eun Jung Lee2,3, Iok In Christine Chio2,3, Chang‐Il Hwang2,3, Hervé Tiriac2,3, Lindsey A. Baker2,3, Dannielle D. Engle2,3, Christine Feig10, Anne Kultti10, Mikala Egeblad5, Douglas T. Fearon5, James M. Crawford11, Hans Clevers12, Youngkyu Park2,3, David A. Tuveson2,3
1Department of Surgical and Perioperative Sciences, Surgery, Umeå University, 901 85 Umeå, Sweden 3
2Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724
3Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724 2
4APC Microbiome Institute and School of Microbiology, University College Cork, Cork, Ireland 4
5Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724 1
6Department of Oncology, Clinica Universidad de Navarra, CIMA, IDISNA, Pamplona 31008, Spain 5
7ARC-Net centre for applied research on cancer, University and Hospital Trust of Verona, 37134 Verona, Italy 6
8Department of Diagnostic and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy 7
9Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794 8
10University of Cambridge, Cancer Research UK, Cambridge Institute, Cambridge, UK 9
11Hofstra Northwell School of Medicine, Hempstead, NY 11550 10
12Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584 CT Utrecht, Netherlands 11

Tóm tắt

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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Journal of Experimental Medicine

Tập 214 Số 3

579-596

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