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Transcriptome Profiling of Ewing Sarcomas

ABSTRACT: Ewing sarcomas (ESs) are aggressive sarcomas driven by EWS fusion genes. We sought to investigate whether whole-transcriptome sequencing (RNA-seq) could be used to detect patterns associated with chemotherapy response or tumor progression after first-line treatment. Transcriptome sequencing (RNA-seq) of 13 ES cases was performed. Among the differen- tially expressed pathways, we identified IGF2 expression as a potential dri- ver of chemotherapy response and progression. We investigated the effect of IGF2 on proliferation, radioresistance, apoptosis, and the transcriptome pattern in four ES cell lines and the effect of IGF2 expression in a valida- tion series of 14 patients. Transcriptome analysis identified differentially expressed genes (adj. P < 0.005) and pathways associated with chemother- apy response (285 genes), short overall survival (662 genes), and progres- sion after treatment (447 genes). Imprinting independent promoter P3- mediated IGF2 expression was identified in a subset of cases with aggres- sive clinical course. In ES cell lines, IGF2 induced proliferation, but pro- moted radioresistance only in CADO cells. High IGF2 expression was also significantly associated with shorter overall survival in patients with ES. Transcriptome analysis of the clinical samples and the cell lines revealed an IGF-dependent signature, potentially related to a stem cell-like phenotype. Transcriptome analysis is a potentially powerful complementary tool to predict the clinical behavior of ES and may be utilized for clinical trial stratification strategies and personalized oncology. Certain gene signatures, for example, IGF-related pathways, are coupled to biological functions that could be of clinical importance. Finally, our results indicate that IGF inhibition may be successful as a first-line therapy in conjunction with conventional radiochemotherapy for a subset of patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270004 | GEO | 2024/06/18

REPOSITORIES: GEO

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Project description:Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have not yet been established. We previously reported that a pan-PI3K inhibitor, ZSTK474, was suggested to be effective for sarcomas in a phase I clinical trial, and demonstrated its efficacy in preclinical model, particularly in cell lines from synovial sarcomas (SS), Ewing’s sarcomas (ES) and alveolar rhabdomyosarcomas (ARMS), all of which harbor chromosomal translocation. Actually, ZSTK474 selectively induced apoptosis in these types of sarcoma cell lines, but the precise mechanism of apoptosis induction remained unclear. Here, we performed transcriptional analyses in SS cell lines including Aska-SS, SYO-1, Yamato-SS and Fuji treated with or without ZSTK474. Gene set enrichment analyses (GSEA) and Gene ontology (GO) analysis revealed that SS cell lines treated with ZSTK474 significantly reduced signatures of PI3K signaling. In addition, upon treatment with ZSTK474, the expression of apoptosis and cell cycle related genes was significantly changed. Importantly, PI3K inhibitors triggered induction of PUMA and BIM, resulting in loss of mitochondrial membrane potential, and the expression knockdown of these genes by RNA interference efficiently suppressed the apoptosis, suggesting their functional involvement in the apoptosis progression. In contrast, TRS-derived cell lines/patient-derived cells from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. These results indicate that PI3K inhibitors selectively induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and subsequent loss of mitochondrial membrane potential, which would be a proof of concept for PI3K-targeted therapy especially for such TRS patients.

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Transcriptome Profiling of Ewing Sarcomas

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