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Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

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Biffi, Giulia 
Daßler-Plenker, Juliane 
Hur, Stella K 
He, Xue-Yan 


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.


Funder: Pershing Square Foundation; FundRef:

Funder: Lustgarten Foundation; FundRef:

Funder: The Cold Spring Harbor Laboratory and Northwell Health Affiliation

Funder: Thompson Family Foundation

Funder: Simons Foundation; FundRef:


Research Article, Cancer Biology, Human Biology and Medicine, TP63, inflammation, cancer-associated fibroblasts, pancreatic cancer, trans-differentiation, squamous, Human, Mouse

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eLife Sciences Publications, Ltd
New York State Department of Health (C150158)
National Cancer Institute (5P01CA013106-Project 4)
National Cancer Institute (CA229699)
Pancreatic Cancer Action Network (16-20-25-VAKO)
National Cancer Institute (5P30CA45508)
National Cancer Institute (5P50CA101955)
National Cancer Institute (P20CA192996)
National Cancer Institute (U10CA180944)
National Cancer Institute (U01CA210240)
National Cancer Institute (U01CA224013)
National Cancer Institute (1R01CA188134)
National Cancer Institute (1R01CA190092)
State of New York (C150158)
Human Frontier Science Program (LT000195/2015 L)
EMBO (ALTF 1203–2014)
Deutsche Forschungsgemeinschaft (DA 2249/1–1)
Deutsche Forschungsgemeinschaft (KL 3228/1–1)