In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.

Journal

Nature genetics

ISSN: 1546-1718

Titre abrégé: Nat Genet

Pays: United States

ID NLM: 9216904

Informations de publication

Date de publication:
03 Sep 2024

Historique:

received: 10 11 2023

accepted: 18 07 2024

medline: 4 9 2024

pubmed: 4 9 2024

entrez: 3 9 2024

Statut: aheadofprint

Résumé

Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR-Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8

Identifiants

DOI: 10.1038/s41588-024-01874-9 PMID: 39227744

pubmed: 39227744

doi: 10.1038/s41588-024-01874-9

pii: 10.1038/s41588-024-01874-9

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : Princess Margaret Cancer Foundation (PMCF)

ID : 886012001223

Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)

ID : 142246, 152863,152864,159567,438793

Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)

ID : FDN-148395

Organisme : Terry Fox Research Institute (Institut de Recherche Terry Fox)

ID : 1090, 1124

Organisme : National Natural Science Foundation of China (National Science Foundation of China)

ID : 31801111

Informations de copyright

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