Somerville, Tim DD, Biffi, Giulia, Daßler-Plenker, Juliane, Miyabayashi, Koji, Xu, Yali, Maia-Silva, Diogo, Klingbeil, Olaf, Demerdash, Osama, Egeblad, Mikala, Tuveson, David, Vakoc, Christopher (2019) Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation. eLife. (Submitted)
Abstract
A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans-differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63-dependent manner. These non cell-autonomous effects occur, at least in part, through TP63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > inflammation diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Egeblad lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab School of Biological Sciences > Publications |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2019 |
| Date Deposited: | 13 Oct 2023 18:09 |
| Last Modified: | 29 Feb 2024 18:42 |
| PMCID: | PMC7200154 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41263 |
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