TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma
Year: 2018
Type: article
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.
Source: Cell Reports
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: American Association for Cancer Research, Lustgarten Foundation, Center for Outcomes Research and Evaluation, Yale School of Medicine, Boehringer Ingelheim, New York State Library, Pershing Square Sohn Cancer Research Alliance, National Institutes of Health, Medical School, University of Michigan, National Cancer Institute
Awards: G1136534092, G1738181864, G2871496085, G2937193396, G4874307829, G4921571990, G4928216548, G4972002595, UAB / UMN SPORE in Pancreatic Cancer, 1/2: Partnership to study racial/ethnic differences in GI cancer biology, G5703899190, G666505512, G7577265389, G789504050, G9000010094, G9000160978, G9000260340, G9000297309, CSHL Cancer Center Support Grant
OpenAlex ID: W2901608487