Oncogene-like addiction to aneuploidy in human cancers

• 成果类型: Article
• 署名作者: Girish, Vishruth; Lakhani, Asad A.; Thompson, Sarah L.; Scaduto, Christine M.; Brown, Leanne M.; Hagenson, Ryan A.; Sausville, Erin L.; Mendelson, Brianna E.; Kandikuppa, Pranav K.; Lukow, Devon A.; Yuan, Monet Lou; Stevens, Eric C.; Lee, Sophia N.; Schukken, Klaske M.; Akalu, Saron M.; Vasudevan, Anand; Zou, Charles; Salovska, Barbora; Li, Wenxue; Smith, Joan C.; Taylor, Alison M.; Martienssen, Robert A.; Liu, Yansheng; Sun, Ruping; Sheltzer, Jason M.
• 署名单位: Yale University; Johns Hopkins University; Cold Spring Harbor Laboratory; Columbia University; Howard Hughes Medical Institute; Cold Spring Harbor Laboratory; University of Minnesota System; University of Minnesota Twin Cities
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8418
• DOI: 10.1126/science.adg4521
• 发表日期: 2023-08-25
• 页码: 848-+
• 关键词: p53; patterns; cells; nucleoside; uridine; disease; rx-3117; census; GROWTH; mdmx

摘要

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.