Oncogene-like addiction to aneuploidy in human cancers.
Vishruth GirishAsad A LakhaniSarah L ThompsonChristine M ScadutoLeanne M BrownRyan A HagensonErin L SausvilleBrianna E MendelsonPranav K KandikuppaDevon A LukowMonet Lou YuanEric C StevensSophia N LeeKlaske M SchukkenSaron M AkaluAnand VasudevanCharles ZouBarbora SalovskaWenxue LiJoan C SmithAlison M TaylorRobert A MartienssenYansheng LiuRuping SunJason M SheltzerPublished in: Science (New York, N.Y.) (2023)
Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT ( Re storing D isomy in A neuploid cells using C RISPR T argeting), 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.