Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma

Abstract

SUMMARY Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histological subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis show that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcoma (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

The landscape of genomic alterations across childhood cancers

“…External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).…”

“…Ninety-five per cent of the patients were under 18 years of age (or age unspecified but confirmed age group paediatric), but available data were included for patients up to 25 years, as these were considered relevant for cancer types that typically peak at a young age. All centres have approved data access and informed consent had been obtained from all patients.External data were downloaded from the European Genome-Phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) using the accession numbers EGAD00001000085, EGAD00001000135, EGAD00001000159, EGAD00001000160, EGAD00001000161, EGAD00001000162, EGAD00001000163, EGAD00001000164, EGAD00001000165, EGAD00001000259, EGAD00001000260, EGAD00001000261, EGAD00001000268, and EGAD00001000269 [49][50][51][52][53][54][55][56][57][58][59][60][61][62] ; internal datasets are related to previous PMIDs 27748748, 27479119, 26923874, 25670083, 25253770, 24972766, 24553142, 25135868, 26632267, 26179511, 24651015, 28726821, 23817572, 25962120, 26294725 17,19,44,63-74 (Supplementary Note 1).The final cohort included 914 individual patients of no more than 25 years of age including primary tumours for 879 patients with 47 matched relapsed tumours, and an additional 35 independent relapsed tumours ( Supplementary Tables 1, 2). Deep-sequencing (~ 30× ) whole-genome data (WGS) were available for 547 samples with matched control, whole-exome sequencing (WES) for 414, and low-coverage whole-genome sequencing (lcWGS) for an additional 54 germline and 186 tumour samples.…”

Uncovering metabolism in rhabdomyosarcoma

“…As a result, p53-deficient cells are characterized by high sugar transport across the cell membrane and high glucose consumption, 2 hallmarks underlying neoplastic transformation. A gene signature consistent with the "p53 off" state has been significantly found in fusion-negative RMS with an incidence from 5% to 19%, 33,89 whereas to a lesser extent in fusion-positive tumors. 42,89 P53 gene inactivation is indeed an experimentally validated cooperating lesion in zebrafish and mouse models of ERMS 29 and ARMS, 25 respectively.…”

“…A gene signature consistent with the "p53 off" state has been significantly found in fusion-negative RMS with an incidence from 5% to 19%, 33,89 whereas to a lesser extent in fusion-positive tumors. 42,89 P53 gene inactivation is indeed an experimentally validated cooperating lesion in zebrafish and mouse models of ERMS 29 and ARMS, 25 respectively. In the human RD cell line, one of the most widely used human ERMS cell lines, 78 loss of p53 activity was reported to rise the glucose uptake by increased expression of the GLUT1 and GLUT4 transporters 83 (Fig.…”

“…17 Whole-genome and RNA sequencing technologies applied to human RMS samples have recently allowed to identify a number of genetic anomalies, especially in ERMS, which would predict susceptibility to oxidative stress 89 (see comments in). 98 In particular, the incidence of RAS pathway mutations was found to increase with ERMS tumor risk group classification, being found in 75% of high-risk ERMS, 45% of intermediate-risk ERMS, and 0% of low-risk ERMS, indicating that deliberate activation of this pathway correlates with ERMS aggressiveness.…”