Year: 2021
Type: preprint
Abstract: Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why ∼50% of Ewing sarcomas, driven by the EWS-FLI1 fusion oncogene, harbor chromosome 8 gains. Expression of the EWS-FLI1 fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates EWS-FLI1-induced replication stress through gain of a copy of RAD21. Low-level ectopic expression of RAD21 is sufficient to dampen replication stress and improve proliferation in EWS-FLI1-expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that RAD21 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.
Source: Genes & Development
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Howard Hughes Medical Institute, Cancer Prevention and Research Institute of Texas, Massachusetts Institute of Technology, Curing Kids Cancer, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, National Institutes of Health, Ludwig Center for Molecular Oncology, Ludwig Center at Harvard, National Cancer Institute, National Institute of General Medical Sciences
Awards: G2360436881, G4774430914, G6342997465, Regulation of mitosis by proteolysis in yeast, G6678588114, Pre-Doctoral Training in Biological Sciences, Dissecting the Pathogenesis of Ewing Sarcoma with Integrative Genomics, Integrating Transforming Approaches to Identify and Target New Vulnerabilities in Cancer, G8824228350, G8859277537, G8863986071, Cancer Center Support (Core) Grant
OpenAlex ID: W3136888944