Although rare overall, rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with a high fatality rate and few treatment options. Moreover, existing laboratory models, although essential, do not fully recapitulate human disease. These limitations, coupled with insufficient availability of paediatric tumour samples, underscore the need for advanced model systems to propel the development of novel therapies.
The guest editors of ‘The RAS Pathway’ Special Issue, Donita Brady and Arvin Dar, highlight the Resource article by Nakahata et al. (2022). In this article, Jason Yustein and colleagues generated a new mouse model that mirrors human RMS on a phenotypic and molecular level through in utero conditional perturbation of tumour suppressor p53 and proto-oncogenic K-Ras (K-RasG12D). Primary tumours in these mice were histologically and anatomically similar to human RMS, and a subpopulation of mice developed metastatic disease. Gene ontology revealed striking similarities between the murine tumours and human RMS. Compared to existing models, which have displayed a mixed phenotype of RMS and undifferentiated pleomorphic sarcoma, this approach more faithfully recapitulates human RMS.
The authors also generated primary cell lines from the mouse tumours. They observed proficient tumour development upon engrafting in immunocompetent wild-type mice, as well as lung metastasis when the cell lines were venously injected. The murine cell lines displayed similar responses to chemotherapies and targeted therapies as human RMS cell lines; therefore, they could be a supplementary model to assess cytotoxicity of novel drugs for RMS.
This new mouse model is, therefore, representative of human RMS and facilitates spontaneous tumour development and progression in an immunocompetent host. This is an advance from previous RMS xenograft models, as it enables the exploration of a wider range of therapies, including immune-modulatory agents. Overall, this mouse model will expand our capabilities to investigate the molecular pathogenesis of RMS and develop more effective and targeted treatments for this devastating paediatric sarcoma.