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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE194355 | GEO | 2022/11/03

REPOSITORIES: GEO

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

Project description:Functional genomic screen in 2D cell culture is limited in identifying therapeutic targets that modulates tumor-microenvironment interaction. Through comparison of targeted CRISPR-Cas9 screens in 2D cell culture and cell line derived xenografts of lung cancer A549, we identified MEN1 as the top hit that confers differential essentialities in vitro and in vivo. Knockout of MEN1 in multiple solid cancer types does not impact cell proliferation in vitro, but significantly promotes and inhibits tumor growth in immunodeficient and immunocompetent mice, respectively. Mechanistically, knockout of MEN1 leads to redistribution of its interaction partner MLL1, a histone methyltransferase, to repetitive genomic regions that produce double stranded RNA. This resulted in MARV and cGAS-STING dependent activation of viral mimicry response, which induces tumor promoting neutrophil and tumor suppressing CD8+ T cell infiltrations in immunodeficient and immunocompetent mice, respectively. Consistently, multiple immune cell infiltrations are negatively correlated with MEN1 abundance and positively correlated with that of MLL1 in patient tumors of a broad range of cancer types. Pharmacological inhibition of MEN1-MLL1 interaction reduces tumor growth in CD8+ T cell dependent manner, and synergizes with anti-PD-L1 treatment. These findings reveal tumor microenvironment dependent oncogenic and tumor suppressive function of MEN1 and provide rationale for therapeutic targeting of MEN1 alone or in combination with immunotherapy in multiple solid cancer types.

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

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro respectively.

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In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [ChIP-seq]

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro.

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In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [CUT & RUN]

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro.

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In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions [A549 RNA-seq]

Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro. Functional genomic screens in 2D cell culture are of limited use for identifying therapeutic targets that modulate tumor cell-microenvironment cell interactions. By comparing targeted CRISPR-Cas9 screens in 2D culture of A549 lung cancer cells versus xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential effects in vitro and in vivo. Knockout of MEN1 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, knockout of MEN1 leads to increased chromatin interaction of its interaction partner MLL1 (KMT2A), a histone methyltransferase, to repetitive genomic regions, where it activates expression of double-stranded RNA. This results in MARV and cGAS-STING dependent activation of viral mimicry response, which induces infiltration of neutrophils and CD8+ T cells in immunodeficient and immunocompetent mice respectively. Consistently, multiple immune cell infiltrations are negatively correlated with MEN1 abundance and positively correlated with that of MLL1 in patient tumors of a broad range of cancer types. Pharmacological inhibition of MEN1-MLL interaction reduces tumor growth in CD8+ T cell dependent manner, with enhanced activity in combination with anti-PD-1 treatment. These findings reveal tumor microenvironment dependent oncogenic and tumor suppressive functions of MEN1 and provide rationale for therapeutic targeting of MEN1 alone or in combination with immunotherapy in multiple solid cancer types.

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Project description:In this study, we used a targeted CRISPR/Cas9 screen to identify genes that determine growth of A549 cells in vivo and in vitro.

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

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

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