二维细胞培养模型中的功能基因组筛选在识别影响肿瘤微环境的治疗靶点方面受到限制。通过将二维培养物中的靶向 CRISPR-Cas9 筛选与来自同一细胞系的异种移植物进行比较，我们确定 MEN1 是最热门的，在体外和体内具有不同的脱落效应。多种实体癌类型中的 MEN1 敲除不会影响体外细胞增殖，但会分别显着促进或抑制免疫缺陷或免疫功能正常小鼠的肿瘤生长。从机制上讲，MEN1 敲除会重新分配 MLL1 染色质占据，增加重复基因组区域的 H3K4me3，激活双链 RNA 表达，并分别增加免疫缺陷和免疫功能正常小鼠的中性粒细胞和 CD8 T 细胞浸润。 menin-MLL 相互作用的药理学抑制以 CD8 T 细胞依赖性方式减少肿瘤生长。这些发现揭示了 MEN1 依赖于肿瘤微环境的致癌和肿瘤抑制功能，并为实体癌中靶向 MEN1 提供了理论依据。© 2024。作者。

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+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin-MLL interaction reduces tumor growth in a CD8+ 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.© 2024. The Author(s).