Marker-based CRISPR screening reveals a MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma.

Autor:	Maia-Silva D; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Schier AC; Dept. of Biochemistry, University of Colorado, Boulder, CO, USA., Skopelitis D; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Kechejian V; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Alpsoy A; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Liverpool J; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Taatjes DJ; Dept. of Biochemistry, University of Colorado, Boulder, CO, USA., Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 27. Date of Electronic Publication: 2023 Oct 27.
DOI:	10.1101/2023.10.24.563848
Abstrakt:	The presence of basal lineage characteristics signifies hyper-aggressive 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 p63, 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 classical PDAC. Taken together, our comprehensive 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. Competing Interests: C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals and Treeline Biosciences; has received research funding from Boehringer-Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. D.J.T. is a member of the SAB at Dewpoint Therapeutics. All other authors declare no competing interests.
Databáze:	MEDLINE
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