As CSC and non-CSC share an identical genetic background, we hypothesize that differences in epigenetics account for the striking functional differences between these two cell populations. Epigenetic mechanisms, such as DNA methylation, play an important role in maintaining pluripotency and regulating the differentiation of stem cells, but the role of DNA methylation in pancreatic CSC is obscure. Using high-throughput methylation analysis, we discovered that sorted CSCs have a higher level of DNA methylation, regardless of the heterogeneity or polyclonality of the CSC populations present in the tumors analyzed. The inhibitory effect we observed was mediated in part through epigenetic reactivation of previously silenced miRNAs, in particular the miR cluster. Although multiple subclonal populations of cancer cells coexist within each tumor and are assumed to drive tumor adaptation and therapeutic failure through Darwinian selection 3 , convincing evidence now demonstrates that cancer heterogeneity is also driven by phenotypic and functional heterogeneity within each of these subclones, resulting in a hierarchical tumor organization 4.
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