研究人员报道了ReDACT（使用CRISPR靶向技术恢复非整倍体细胞的分裂），这是一套染色体工程化工具，并能够消除癌症基因组中特定的非整倍体。利用ReDACT，研究人员创建了一个具有或缺乏常见非整倍体的同源细胞群体，并且证明了1q染色体三体是带有这种改变的癌症的恶性生长所需的。
从机制上讲，获得1q染色体会增加MDM4的表达并抑制p53信号，研究人员表明TP53突变与人类癌症中的1q非整倍体是相互排斥的。因此，肿瘤细胞可以依赖特定的非整倍体，这就提出了这些“非整倍体成瘾”可以作为一种治疗策略的靶点。
据了解，大多数癌症都表现出非整倍体，但其在肿瘤发展中的功能意义是有争议的。
附：英文原文
Title: Oncogene-like addiction to aneuploidy in human cancers
Author: Vishruth Girish, Asad A. Lakhani, Sarah L. Thompson, Christine M. Scaduto, Leanne M. Brown, Ryan A. Hagenson, Erin L. Sausville, Brianna E. Mendelson, Pranav K. Kandikuppa, Devon A. Lukow, Monet Lou Yuan, Eric C. Stevens, Sophia N. Lee, Klaske M. Schukken, Saron M. Akalu, Anand Vasudevan, Charles Zou, Barbora Salovska, Wenxue Li, Joan C. Smith, Alison M. Taylor, Robert A. Martienssen, Yansheng Liu, Ruping Sun, Jason M. Sheltzer
Issue&Volume: 2023-07-06
Abstract: 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.
DOI: adg4521
Source: https://www.science.org/doi/10.1126/science.adg4521