视网膜母细胞瘤
转录组
生物
癌症研究
抑制器
斑马鱼
视网膜母细胞瘤蛋白
体内
细胞
基因
遗传学
细胞周期
基因表达
作者
Matthew G. Field,Jeffim N. Kuznetsoff,Michelle G. Zhang,James J. Dollar,Michael A. Durante,Yoseph Sayegh,Christina L. Decatur,Stefan Kurtenbach,Daniel Pelaez,J. William Harbour
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2022-08-19
卷期号:8 (33)
被引量:9
标识
DOI:10.1126/sciadv.abm8466
摘要
Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify previously unknown Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death, which is exacerbated in hypoxia. These findings reveal a previously unidentified dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.
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