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Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. DOI: http://dx.doi.org/10.7554/eLife.12116.001, eLife digest Soft tissue sarcomas are rare cancers that originate in tissues such as muscles, tendons, cartilage and fat. These cancers are further classified into subtypes based on their appearance. For example, rhabdomyosarcoma cells resemble the cells that normally develop into muscle, while other soft tissue tumors that do not look like a distinct cell type are called undifferentiated pleomorphic sarcomas. Recent experiments have suggested that although these subtypes appear different, they may both arise from the cells that build muscles. However, this had not been confirmed. Morena et al. investigated whether changing the environment – also known as the “niche” – of muscle stem cells could influence what type of sarcoma developed in mice that were prone to cancer. Normally muscle stem cells in an adult only regenerate injured muscles, and need to receive the correct cues before they divide. Among these cues is a protein called Hepatocyte Growth Factor (or HGF for short), which is produced by cells in the muscle stem cells’ niche. Morena et al. engineered mice so that the production of HGF in the muscles could be switched on or off at will. Mice that were already prone to cancer and produced a lot of HGF tended to develop rhabdomyosarcomas. However, when HGF was turned on in similar mice that also lacked normal muscle stem cells, the resulting sarcomas were predominantly undifferentiated pleomorphic sarcomas. These data indicate that rhabdomyosarcomas probably originate from muscle stem cells, whereas undifferentiated pleomorphic sarcomas develop from other cells in the niche. Lastly, Morena et al. studied the sarcomas in their mice in more detail and observed that, similar to what has been found in human rhabdomyosarcomas, individual tumors had different genetic mutations. These differences make it difficult to treat sarcomas with a single anti-cancer drug. However, the new results suggest that a combination of targeted drugs may prove effective in blocking tumor growth and in preventing resistance. DOI: http://dx.doi.org/10.7554/eLife.12116.002