Dissecting cancer biology with iPS cell technology

抄録

Cancer arises through the accumulations of both genetic and epigenetic alterations. Although the causal role of genetic mutations on cancer development has been established in vivo, similar evidence for epigenetic alterations is still limited. Moreover, mutual interactions between genetic mutations and epigenetic alterations remain unclear. Cellular reprogramming technology can be used to actively modify the epigenome without affecting the genomic information. Here I introduce our recent studies that utilized this property for cancer research.

　Cell type-specificity of cancer development has long been recognized. However, the underlying mechanism how particular genetic mutations transform a specific cell type remains unclear. Clear cell sarcoma (CCS), which is a rare soft tissue sarcoma caused by 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. Taking advantage of the one-step, cell type-specific sarcoma model, we identified a cell-of-origin for these sarcomas. Furthermore, we showed that EWS/ATF1 is preferentially recruited at enhancer of the cell-of-origin in CCS cells. All together, cancer cell reprogramming uncovered cell-of-origin for CCSs and provided a molecular basis for cell type specificity of cancer development.