Targeted Inactivation of Oncogenic Drivers of Cancer Originating in Adult Stem Cells during Muscle Regeneration

The most prevalent types of cancer primarily affect tissuescontaining cells with increased proliferative potential ofteninferred by resident stem cells (SC) that enable regenerationof the respective tissue. Skeletal muscle regeneration is mediatedby activation of rare quiescent muscle SCs that expressPax۷. Recently it was shown that germline inactivation of p۵۳in mdx mice undergoing chronic muscle regeneration developrhabdomyosarcomas (RMS). However the cancer cell of originand mechanisms of tumor formation under these settingshave remained elusive. Coupling genetic lineage tracing andgenomic analyses, we identified muscle SCs as a cellular originof RMS and show that deactivation of muscle SC quiescenceby regeneration is necessary to generate RMS upon SC specificloss of p۵۳. Purification of lineage-traced tumor cells enabledidentification of discrete genomic copy number amplificationsthat drive tumorigenesis including but not limited to yap۱, cmet,cdk۴/os۹ and c-jun. By reanalyzing human sequencingdata including the TCGA PANCAN data set comprising morethan ۱۰,۰۰۰ patients across a broad range of human cancers wediscovered novel molecular subtypes of cancer. Importantly,targeted inactivation of identified oncogenes in individual primarytumor cells abolished tumor expansion. Our data indicatethe dependence of individual tumors on distinct regulatory networksthat originate from adult SCs and underscore the neces sity to provide means for personalized therapeutic interventionsof cancer