近日，加拿大多伦多大学Housheng Hansen He等研究人员合作发现，在体CRISPR筛选揭示MEN1在调控肿瘤与微环境相互作用中的双重功能。相关论文于2024年9月3日在线发表在《自然—遗传学》杂志上。

通过比较在二维培养和源自相同细胞系的异种移植瘤中进行的靶向CRISPR-Cas9筛选，研究人员发现MEN1是体外和体内表现出不同脱靶效应的最显著基因。MEN1敲除在多种实体癌中并不影响体外细胞增殖，但在免疫缺陷或免疫健全的小鼠中分别显著促进或抑制肿瘤生长。

从机制上看，MEN1敲除会重新分布MLL1染色质占位，增加H3K4me3在重复基因组区域的标记，激活双链RNA表达，并在免疫缺陷和免疫健全的小鼠中分别增加中性粒细胞和CD8⁺ T细胞的浸润。药理学抑制menin-MLL相互作用会以CD8⁺ T细胞依赖的方式减少肿瘤生长。这些发现揭示了MEN1在肿瘤微环境中的致癌和抑癌双重功能，并为靶向MEN1治疗实体癌提供了依据。

据悉，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存在局限性。

附：英文原文

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

Author: Su, Peiran, Liu, Yin, Chen, Tianyi, Xue, Yibo, Zeng, Yong, Zhu, Guanghui, Chen, Sujun, Teng, Mona, Ci, Xinpei, Guo, Mengdi, He, Michael Y., Hao, Jun, Chu, Vivian, Xu, Wenxi, Wang, Shiyan, Mehdipour, Parinaz, Xu, Xin, Marhon, Sajid A., Soares, Fraser, Pham, Nhu-An, Wu, Bell Xi, Her, Peter Hyunwuk, Feng, Shengrui, Alshamlan, Najd, Khalil, Maryam, Krishnan, Rehna, Yu, Fangyou, Chen, Chang, Burrows, Francis, Hakem, Razqallah, Lupien, Mathieu, Harding, Shane, Lok, Benjamin H., OBrien, Catherine, Berlin, Alejandro, De Carvalho, Daniel D., Brooks, David G., Schramek, Daniel, Tsao, Ming-Sound, He, Housheng Hansen

Issue&Volume: 2024-09-03

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+ 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. Loss of MEN1 affects tumor growth, varing with the components of the tumor microenvironment. These tumors show redistribution of MLL1 on chromatin and the activation of a viral mimicry response.

DOI: 10.1038/s41588-024-01874-9

Source: https://www.nature.com/articles/s41588-024-01874-9