@article{60d25d72578b490eb4dd3a54f7f53205,
title = "RB1 loss triggers dependence on ESRRG in retinoblastoma",
abstract = "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.",
author = "Field, {Matthew G.} and Kuznetsoff, {Jeffim N.} and Zhang, {Michelle G.} and Dollar, {James J.} and Durante, {Michael A.} and Yoseph Sayegh and Decatur, {Christina L.} and Stefan Kurtenbach and Daniel Pelaez and Harbour, {J. William}",
note = "Funding Information: We acknowledge the support of the Sylvester Comprehensive Cancer Center Biostatistics and Bioinformatics Shared Resource (BBSR) and Oncogenomics Shared Resource (OGSR) and the University of Miami Institute for Data Science and Computing (IDSC). This work was supported by the Alex{\textquoteright}s Lemonade Stand/Tap Cancer Out Innovation Grant (to J.W.H. and D.P.), University of Miami Sheila and David Fuente Graduate Program in Cancer Biology (to M.G.F., M.A.D., M.G.Z., and J.J.D.), University of Miami Center for Computational Science Fellowship (to M.G.F. and M.A.D.), University of Miami Lois Pope LIFE Fellowship Award (to M.G.F.), Alcon Research Award (to J.W.H.), NIH/NCI R01CA248890 (to D.P. and J.W.H.), NIH/NCI P30CA240139 (Sylvester Comprehensive Cancer Center), NIH/NEI P30EY014801 (Bascom Palmer Eye Institute), Research to Prevent Blindness Unrestricted Grant (Bascom Palmer Eye Institute), and a philanthropic gift from M. J. Daily (to J.W.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",
year = "2022",
month = aug,
day = "19",
doi = "10.1126/sciadv.abm8466",
language = "English (US)",
volume = "8",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "33",
}