Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation.

Autor:	Somerville TD; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Biffi G; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, United States.; Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Daßler-Plenker J; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Hur SK; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., He XY; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Vance KE; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States., Miyabayashi K; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, United States., Xu Y; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Maia-Silva D; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.; Watson School of Biological Sciences, Cold Spring Harbor, United States., Klingbeil O; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Demerdash OE; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Preall JB; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Hollingsworth MA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States., Egeblad M; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States., Tuveson DA; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, United States., Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Apr 24; Vol. 9. Date of Electronic Publication: 2020 Apr 24.
DOI:	10.7554/eLife.53381
Abstrakt:	A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A and CXCL1 as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment. Competing Interests: TS, GB, JD, SH, XH, KV, KM, YX, DM, OK, OD, JP, MH, ME No competing interests declared, DT an advisor to Surface, Leap, and Cygnal and has stock ownership in Surface and Leap, CV has received funding from Boehringer-Ingelheim and is an advisor to KSQ Therapeutics. (© 2020, Somerville et al.)
Databáze:	MEDLINE
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