Oncogene-like addiction to aneuploidy in human cancers
Oncogene-like addiction to aneuploidy in human cancers
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DOI：
10.1126/science.adg4521
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发表时间：
2023-08-25
期刊：
影响因子：
56.9
通讯作者：
Sheltzer, Jason M.
中科院分区：
文献类型：
--
作者：
Girish, Vishruth;Lakhani, Asad A.;Sheltzer, Jason M.
大多数癌症表现出非整倍体，但其在肿瘤发展中的功能意义是有争议的。在这里，我们描述了ReDACT（使用CRISPR靶向恢复非整倍体细胞中的二体性），这是一套染色体工程工具，使我们能够从癌症基因组中消除特定的非整倍体。使用ReDACT，我们创建了一组具有或缺乏常见非整倍性的同基因细胞，我们证明了染色体1q的三体性是携带这种改变的癌症恶性生长所必需的。从机制上讲，获得染色体1q增加了MDM4的表达并抑制了p53信号传导，我们表明TP53突变与人类癌症中的1q非整倍体相互排斥。因此，肿瘤细胞可以依赖于特定的非整倍体，提高了这些“非整倍体成瘾”可以作为治疗策略的可能性。
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these "aneuploidy addictions" could be targeted as a therapeutic strategy.