Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

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)

DOI: 10.1101/833046


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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