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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, 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196420 | GEO | 2022/08/24

REPOSITORIES: GEO

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Project description:Chemotherapy resistance is one of the reasons for the loss of the eye in retinoblastoma (RB) pa-tients. RB chemotherapy resistance has been investigated in different cell culture models like WERI RB1. Furthermore, chemotherapy resistant RB subclones like the etoposide resistant WERI ETOR cell line have been established to improve understanding of chemotherapy resistance in RB. Ob-jective of this study was to characterize the cell line models of an etoposide sensitive WERI RB1 and its etoposide resistant subclone WERI ETOR by proteomics analysis. Subsequently, quantitative proteomic data served for correlation analysis with known drug perturbation profiles. . WERI RB1 and WERI ETOR were cultured and prepared for quantitative mass spectrometry. Comparative proteomic profiling was performed with electrospray ionization tandem mass spectrometry in data-independent acquisition mode (SWATH). The raw SWATH files were processed using neural networks in library free mode along with machine learning algorithms. Pathway enrichment was performed using the REACTOME pathway resource and correlated to the Molecular Signature Database (MSigDB) hallmark gene set collections for functional annotation. Also, a drug connec-tivity analysis using the L1000 database was used to correlate the mechanism-of-action (MOA) for different anticancer reagents to WERI RB1 / WERI ETOR signatures. A total 4,756 proteins were identified across all samples which revealed a distinct clustering between groups. Of these pro-teins, 64 proteins were significantly altered (q < 0.05 & log2FC |>2|, 22% higher in WERI ETOR). Pathway analysis showed an enriched metabolic pathway for retinoid metabolism and transport pathway in WERI ETOR and for sphingolipid de novo biosynthesis in WERI RB1. In addition, this study showed similar protein signatures of topoisomerase inhibitors and WERI ETOR as well as of ATPase inhibitors, acetylcholine receptor antagonists and VEGFR inhibitors and WERI RB1. In this study, WERI RB1 and WERI ETOR were characterized as a cell line model for chemotherapy re-sistance in RB by using data-independent mass spectrometry. The global proteome revealed the activation of sphingolipid de novo biosynthesis in WERI RB1 and potential treatment options for etoposide resistant RB.

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RB1 loss triggers dependence on ESRRG in retinoblastoma

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