@article{f67aaf3b679849b8a1d1038aaa204795,
title = "Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation",
abstract = "A highly aggressive subset of pancreatic ductal adenocarcinomas undergo transdifferentiation 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.",
author = "Somerville, {Tim D.D.} and Giulia Biffi and Juliane Da{\ss}ler-Plenker and Hur, {Stella K.} and He, {Xue Yan} and Vance, {Krysten E.} and Koji Miyabayashi and Yali Xu and Diogo Maia-Silva and Olaf Klingbeil and Demerdash, {Osama E.} and Preall, {Jonathan B.} and Hollingsworth, {Michael A.} and Mikala Egeblad and Tuveson, {David A.} and Vakoc, {Christopher R.}",
note = "Funding Information: The authors would like to thank the Cold Spring Harbor Cancer Center Support Grant (CCSG) shared resources: Bioinformatics Shared Resource, Next Generation Sequencing Core Facility, R Rubino and J Habel Animal Resources for technical assistance with the mouse transplantation assays, P Moody and C Viola in the Flow Cytometry Facility, Animal and Tissue Imaging, and the Animal Facility. TDDS was supported by a grant from the State of New York, contract no. C150158. CRV was supported by Pershing Square Sohn Cancer Research Alliance, the Cold Spring Harbor Laboratory and Northwell Health Affiliation, the National Cancer Institute (NCI) 5P01CA013106-Project 4 and 1RO1CA229699, and a Career Development Award from the Pancreatic Cancer Action Network-American Association for Cancer Research (AACR) 16-20-25-VAKO. XYH was supported by a grant from the State of New York, contract no. C150158. This work was supported by the Lustgarten Foundation, where DAT is a distinguished scholar and Director of the Lustgarten Foundation–designated Laboratory of Pancreatic Cancer Research. DAT is also supported by the Cold Spring Harbor Laboratory Association and the National Institutes of Health (NIH 5P30CA45508, 5P50CA101955, P20CA192996, U10CA180944, U01CA210240, U01CA224013, 1R01CA188134, and 1R01CA190092). CRV, DAT, and ME were supported by the Thompson Family Foundation and Simons Foundation. In addition, we are grateful for support from the following: the Human Frontiers Science Program (LT000195/2015 L for GB), EMBO (ALTF 1203–2014 for GB), Deutsche Forschungs-gemeinschaft (DFG) Research Fellowship (DA 2249/1–1 for JDP; KL 3228/1–1, for OK). Publisher Copyright: {\textcopyright} 2020, eLife Sciences Publications Ltd. All rights reserved.",
year = "2020",
month = apr,
doi = "10.7554/eLife.53381",
language = "English (US)",
volume = "9",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}