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

Cell Rep. 2018 Nov 13;25(7):1741-1755.e7. 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 (ΔNp63) 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.

Keywords: H3K27ac; TP63; chromatin; enhancer; enhancer reprogramming; master regulator; squamous.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • Humans
  • Mice
  • Phenotype
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Tumor Suppressor Proteins / metabolism*

Substances

  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins