TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma

Somerville, T. D. D., Xu, Y., Miyabayashi, K., Tiriac, H., Cleary, C. R., Maia-Silva, D., Milazzo, J. P., Tuveson, D. A., Vakoc, C. R. (November 2018) TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma. Cell Rep, 25 (7). 1741-1755.e7. ISSN 2211-1247

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URL: https://www.ncbi.nlm.nih.gov/pubmed/30428345
DOI: 10.1016/j.celrep.2018.10.051

Abstract

The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (DeltaNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > TP63
CSHL Authors:
Communities: CSHL labs > Tuveson lab
CSHL labs > Vakoc lab
Watson School > Publications
Depositing User: Matthew Dunn
Date: 13 November 2018
Date Deposited: 27 Nov 2018 17:29
Last Modified: 03 Jan 2019 22:01
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37486

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