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 (Public Dataset)
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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 Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Tuveson lab CSHL labs > Vakoc lab School of Biological Sciences > Publications CSHL Cancer Center Shared Resources > Animal Shared Resource |
| Depositing User: | Matthew Dunn |
| Date: | 13 November 2018 |
| Date Deposited: | 27 Nov 2018 17:29 |
| Last Modified: | 09 Nov 2020 21:51 |
| PMCID: | PMC6296757 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/37486 |
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