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

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.