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Updated: Aug 31, 2025
Reconstruct Human Retinoblastoma In Vitro
Published on: October 11, 2022
RB1 loss triggers dependence on ESRRG in retinoblastoma
Matthew G Field1,2, Jeffim N Kuznetsoff1, Michelle G Zhang1
1Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center, and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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.
Insights
This study identifies estrogen-related receptor gamma (ESRRG) as a key dependency in retinoblastoma (Rb), a childhood eye cancer. Targeting ESRRG offers a promising new therapeutic strategy for Rb, especially in hypoxic conditions.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Retinoblastoma (Rb) is a severe childhood eye cancer often initiated by RB1 tumor suppressor inactivation.
- Current treatments for Rb use nonspecific chemotherapeutics, leading to resistance and toxicity.
Purpose of the Study:
- To identify novel therapeutic vulnerabilities in retinoblastoma (Rb).
- To investigate the role of estrogen-related receptor gamma (ESRRG) in Rb pathogenesis.
Main Methods:
- Analysis of 103 whole exomes, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors.
- Investigated the interaction between RB1 and ESRRG.
- Assessed the effect of ESRRG depletion or inhibition on Rb cell death, particularly in hypoxic conditions.
Main Results:
- Recurrent genomic aberrations implicated ESRRG in Rb.
- RB1 loss leads to the uncoupling of ESRRG from negative regulation.
- ESRRG regulates retinogenesis and oxygen metabolism genes in Rb cells.
- ESRRG is upregulated in hypoxic Rb cells.
- ESRRG depletion or inhibition induced significant Rb cell death, enhanced by hypoxia.
Conclusions:
- Rb cells exhibit a previously unrecognized dependency on ESRRG.
- ESRRG represents a potential therapeutic target for retinoblastoma.
- Targeting ESRRG may overcome treatment resistance and toxicity associated with current therapies.
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