Field Matthew G, Kuznetsoff Jeffim N, Zhang Michelle G, Dollar James J, Durante Michael A, Sayegh Yoseph, Decatur Christina L, Kurtenbach Stefan, Pelaez Daniel, Harbour J William
Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center, and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA 52242, USA.
Sci Adv. 2022 Aug 19;8(33):eabm8466. doi: 10.1126/sciadv.abm8466.
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.
视网膜母细胞瘤（Rb）是一种致命的儿童眼部癌症，其典型发病机制是RB1肿瘤抑制因子失活。临床治疗仍依赖于非特异性化疗药物，这些药物与治疗耐药性和毒性相关。在此，我们分析了来自原发性Rb肿瘤的103个全外显子组、20个全转录组、5个单细胞转录组和4个全基因组，以确定此前未知的Rb细胞依赖因素。几种反复出现的基因组畸变表明雌激素相关受体γ（ESRRG）参与Rb发病机制。RB1直接与ESRRG相互作用并抑制ESRRG，RB1缺失使ESRRG摆脱负调控。ESRRG调节Rb细胞中参与视网膜生成和氧代谢的基因。ESRRG在体内缺氧的Rb细胞中优先表达。ESRRG的缺失或抑制导致明显的Rb细胞死亡，在缺氧条件下这种死亡会加剧。这些发现揭示了Rb细胞此前未被识别的对ESRRG的依赖，并表明ESRRG是Rb潜在的治疗靶点。
