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

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<sup>+</sup> T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin-MLL interaction reduces tumor growth in a CD8<sup>+</sup> T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.

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Publication Details

Journal
Nature Genetics
Published
2024-09-01
DOI
https://doi.org/10.1038/s41588-024-01874-9
Citations
22
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
5.29

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article

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

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Nature Genetics
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article

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

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article en
22 citations

Abstract

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<sup>+</sup> T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin-MLL interaction reduces tumor growth in a CD8<sup>+</sup> T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.

Nature GeneticsVol. 56(9)
Tongji University (CN), Mount Sinai Hospital (CA), University Health Network (CA), Sun Yat-sen University (CN), University of Toronto (CA), Lunenfeld-Tanenbaum Research Institute (CA), Sichuan University (CN), Princess Margaret Cancer Centre (CA), University of Oxford (GB), Ludwig Cancer Research (GB), Shanghai Pulmonary Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Kura Oncology (United States) (US), State Key Laboratory of Biotherapy
Princess Margaret Cancer Foundation, National Natural Science Foundation of China, Terry Fox Research Institute, Canadian Institutes of Health Research
Zero hunger
Openalex Percentile: Top 4%
Phagocytosis and Immune Regulation
5.29
DOIOpen Access PDFOpenAlex
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