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Transcriptome profiling of Ewing sarcomas - treatment resistance pathways and IGF-dependency.

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 differentially expressed pathways, we identified IGF2 expression as a potential driver 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 validation series of 14 patients. Transcriptome analysis identified differentially expressed genes (adj. P < 0.005) and pathways associated with chemotherapy response (285 genes), short overall survival (662 genes), and progression after treatment (447 genes). Imprinting independent promoter P3-mediated IGF2 expression was identified in a subset of cases with aggressive clinical course. In ES cell lines, IGF2 induced proliferation, but promoted 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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7191197 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Transcriptome profiling of Ewing sarcomas - treatment resistance pathways and IGF-dependency.

Chen Yi Y Hesla Asle C AC Lin Yingbo Y Ghaderi Mehran M Liu Mingzhi M Yang Chen C Zhang Yifan Y Tsagkozis Panagiotis P Larsson Olle O Haglund Felix F

Molecular oncology 20200313 5

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 differentially expressed pathways, we identified IGF2 expression as a potential driver of chemotherapy response and progression. We investigated the effect of ...[more]

PMID: 32115849

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Project description:UnlabelledWe showed that unloading markedly diminished the effects of IGF-I to activate its signaling pathways, and the disintegrin echistatin showed a similar block in osteoprogenitor cells. Furthermore, unloading decreased alphaVbeta3 integrin expression. These results show that skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways at least in part through downregulation of integrin signaling.IntroductionWe have previously reported that skeletal unloading induces resistance to insulin-like growth factor-I (IGF-I) with respect to bone formation. However, the underlying mechanism remains unclear. The aim of this study was to clarify how skeletal unloading induces resistance to the effects of IGF-I administration in vivo and in vitro with respect to bone formation.Materials and methodsWe first determined the response of bone to IGF-I administration in vivo during skeletal unloading. We then evaluated the response of osteoprogenitor cells isolated from unloaded bones to IGF-I treatment in vitro with respect to activation of the IGF-I signaling pathways. Finally we examined the potential role of integrins in mediating the responsiveness of osteoprogenitor cells to IGF-I.ResultsIGF-I administration in vivo significantly increased proliferation of osteoblasts. Unloading markedly decreased proliferation and blocked the ability of IGF-I to increase proliferation. On a cellular level, IGF-I treatment in vitro stimulated the activation of its receptor, Ras, ERK1/2 (p44/42 MAPK), and Akt in cultured osteoprogenitor cells from normally loaded bones, but these effects were markedly diminished in cells from unloaded bones. These results were not caused by altered phosphatase activity or changes in receptor binding to IGF-I. Inhibition of the Ras/MAPK pathway was more impacted by unloading than that of Akt. The disintegrin echistatin (an antagonist of the alphaVbeta3 integrin) blocked the ability of IGF-I to stimulate its receptor phosphorylation and osteoblast proliferation, similar to that seen in cells from unloaded bone. Furthermore, unloading significantly decreased the mRNA levels both of alphaV and beta3 integrin subunits in osteoprogenitor cells.ConclusionThese results indicate that skeletal unloading induces resistance to IGF-I by inhibiting the activation of IGF-I signaling pathways, at least in part, through downregulation of integrin signaling, resulting in decreased proliferation of osteoblasts and their precursors.

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Transcriptome profiling of Ewing sarcomas - treatment resistance pathways and IGF-dependency.

Publications

Transcriptome profiling of Ewing sarcomas - treatment resistance pathways and IGF-dependency.

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