Grant: CIHR Fellowship

Rhabdomyosarcoma (RMS) is a devastating muscle cancer in children and adolescents. RMS has an incidence of four cases per million children in Canada, making it one of the most common cancers that arise from soft tissue. Spindle cell/sclerosing RMS (SC/SRMS) is primarily caused by gain-of-function mutations in the MYOD1 transcription factor (MYODL122R) and is the most aggressive subtype of RMS. Patients with SC/SRMS have poor responses to standard treatment that includes radiation and chemotherapy. There are currently limited targeted therapies for SC/SRMS, partly a result of RMS treatment strategies having not changed in decades. My project will uncover new mechanisms that drive aggression and therapy resistance in MYOD1-mutated SC/SRMS. My work will identify roles for MYODL122R on (i) inducing new Core Regulatory Circuits (CRC) and (ii) regulating novel genes that drive growth, aggression, and therapy resistance. The CRC refers to the collection of transcription factors that coordinately bind to the same genomic regions to control gene expression associated with cell identity, state, and malignancy. My central hypothesis is that MYOD1L122R induces a novel CRC and consequently transcriptionally turns on cellular pathways that drive aggression and therapy resistance in SC/SRMS. Aim 1 will assess the role MYOD1L122R in establishing a novel CRC to control transcriptional changes associated with aggression and therapy resistance. Aim 2 will uncover mechanisms by which MYODL122R drive growth, aggression, and therapy resistance in SC/SRMS. This work will use a CRISPR/Cas9 drop out screen to identify essential genes in MYOD1L122R-mediated SC/SRMS and then mechanistic studies will uncover the precise molecular pathways by which these factors drive growth, aggression, and therapy responses. My project will provide a better understanding of how MYOD1 mutations mechanistically cause RMS and ultimately identify novel therapeutic targets for SC/SRMS.