RB1 loss triggers dependence on ESRRG in retinoblastoma

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, 16 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify novel 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 novel dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb. RNA-Sequencing of primary retinoblastoma tumors, RNA-Sequencing of low-passaged primary cultured retinoblastoma cell lines with and without knockdown of ESRRG, ChIP-Sequencing of low-passaged retinoblastoma cell lines with pulldown of ESRRG

视网膜母细胞瘤（Retinoblastoma, Rb）是一种致命性儿童眼部恶性肿瘤，其经典发病机制为RB1肿瘤抑制基因失活。目前临床治疗仍依赖非特异性化疗药物，但这类药物易引发治疗耐药与毒性反应。本研究对103例原发性Rb肿瘤的全外显子组、16例全转录组、5例单细胞转录组以及4例全基因组进行测序分析，以鉴定Rb的新型依赖靶点。多项复发性基因组异常提示，雌激素相关受体γ（Estrogen-related receptor gamma, ESRRG）参与Rb的发病进程。RB1可直接结合并抑制ESRRG，RB1缺失会解除对ESRRG的负向调控。ESRRG可调控Rb细胞中参与视网膜发生与氧代谢的相关基因。在体内，ESRRG在缺氧Rb细胞中呈优先表达状态。敲低或抑制ESRRG会显著诱导Rb细胞死亡，且该效应在缺氧条件下会进一步增强。本研究揭示了Rb细胞对ESRRG的新型依赖关系，并提示ESRRG可作为Rb潜在的治疗靶点。本研究的测序数据集包括：原发性视网膜母细胞瘤肿瘤的RNA测序、经ESRRG敲低或未敲低的低传代原发性培养Rb细胞系的RNA测序，以及针对ESRRG进行免疫沉淀下拉富集的低传代Rb细胞系的染色质免疫沉淀测序（ChIP-Sequencing）。