Tumor and Stem Cell Biology EpigeneticStatesofCells ofOrigin andTumorEvolutionDrive Tumor-Initiating Cell Phenotype and Tumor Heterogeneity

A central confounding factor in the development of targeted therapies is tumor cell heterogeneity, particularly in tumor-initiating cells (TIC), within clinically identical tumors. Here, we show how activation of the Sonic Hedgehog (SHH) pathway in neural stem and progenitor cells creates a foundation for tumor cell evolution to heterogeneous states that are histologically indistinguishable but molecularly distinct. In spontaneous medulloblastomas that arise in Patched (Ptch)þ/ mice, we identified three distinct tumor subtypes. Through cell type– specific activation of the SHH pathway in vivo, we determined that different cells of origin evolved in unique ways to generate these subtypes.Moreover, TICs in each subtype had distinctmolecular and cellular phenotypes. At the bulk tumor level, the three tumor subtypes could be distinguished by a 465-gene signature and by differential activation levels of the ERK and AKT pathways. Notably, TICs fromdifferent subtypes were differentially sensitive to SHHor AKTpathway inhibitors, highlighting newmechanisms of resistance to targeted therapies. In summary, our results show how evolutionary processes act on distinct cells of origin to contribute to tumoral heterogeneity, at both bulk tumor and TIC levels. Cancer Res; 74(17); 4864–74. 2014 AACR.