Exome sequencing of clear cell sarcoma and sarcoma-iPSC. Mus musculus

Cell type-specificity of cancer development has long been recognized, however, the underlying mechanism for how particular genetic mutations transform a specific cell type to a cancerous remains unclear. Clear cell sarcoma (CCS), which is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene, resembles malignant melanoma, and thus is known as malignant melanoma of soft parts. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice developed secondary sarcomas immediately after EWS/ATF1 induction, but the sarcomas arose exclusively in the soft tissue. Despite the presence of multiple genetic aberrations, EWS/ATF1 expression induces oncogene-induced senescence (OIS) in most cell types in sarcoma-iPSC mice, whereas it actively prevents senescence in sarcoma cells, implying the opposing effects of EWS/ATF1 expression on premature senescence depending on cellular context. Taking advantage of the one-step, cell type-specific sarcoma model, we identified Tppp3-expressing neural crest cell (NCC)-derived cells in peripheral nerves, but not melanocytes, as a cell-of-origin for these sarcomas. Furthermore, we showed cell type-specific recruitment of EWS/ATF1 and identified NCC-related enhancers as a target of EWS/ATF1 binding in CCS cells. Finally, epigenetic silencing at the cell-type specific enhancer induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, these results show that cancer cell reprogramming can uncover unappreciated cell-of-origin for CCSs and reveal a molecular basis for cell type-specificity of CCS development, which provides a novel therapeutic target.