Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma

Maia-Silva, Diogo, Cunniff, Patrick J, Schier, Allison C, Skopelitis, Damianos, Trousdell, Marygrace C, Moresco, Philip, Gao, Yuan, Kechejian, Vahag, He, Xue-Yan, Sahin, Yunus, Wan, Ledong, Alpsoy, Aktan, Liverpool, Jynelle, Krainer, Adrian R, Egeblad, Mikala, Spector, David L, Fearon, Douglas T, Dos Santos, Camila O, Taatjes, Dylan J, Vakoc, Christopher R (June 2024) Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma. Nature Genetics. ISSN 1061-4036

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URL: https://www.ncbi.nlm.nih.gov/pubmed/38886586

DOI: 10.1038/s41588-024-01790-y

Abstract

The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Cunniff, Patrick Skopelitis, Damianos Trousdell, Marygrace C Moresco, Philip Gao, Yuan He, Xueyan Wan, Ledong Krainer, Adrian R. Egeblad, Mikala Spector, David L. Fearon, Douglas Dos Santos, Camila O. Vakoc, Christopher R. Maia-Silva, Diogo Kechejian, Vahag Sahin, Yunus Alpsoy, Aktan Liverpool, Jynelle
Communities:	CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Dos Santos lab CSHL labs > Egeblad lab CSHL labs > Fearon lab CSHL labs > Krainer lab CSHL labs > Spector lab CSHL labs > Vakoc lab CSHL labs > Van Aelst lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	17 June 2024
Date Deposited:	18 Jun 2024 19:21
Last Modified:	12 Jul 2024 15:40
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41584

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