Induced pluripotent stem cell technology for dissecting the cancer epigenome

Abstract

Cancer arises through the accumulation 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 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 underlying genomic sequences. Here we introduce recent studies that have utilized this property for cancer research. We propose that just as it has potential for regenerative medicine and disease modeling, cell reprogramming could also be a powerful tool for dissecting the role of the cancer epigenome in the development and maintenance of cancer cells.

Keywords: Cancer epigenetics; DNA methylation; cancer model; iPS cell; reprogramming.

Figure 1

Crosstalk between genomic and epigenetic abnormalities during cancer development. Cancer arises from a somatic cell accumulating genetic and epigenetic abnormalities. During its progression, external factors cause additional genetic and epigenetic changes in the cell. The genetic abnormalities can regulate the epigenetics via alterations in transcriptional networks. In contrast, the epigenetic abnormalities can regulate genomic integrity through chromosomal instabilities.

Figure 2

Application of cell reprogramming to cancer biology. (a) Cell reprogramming can alter the epigenome of a cancer without affecting genetic abnormalities. (b) Cell reprogramming as a tool for dissecting the unique properties of cancer cells. (1) Reprogramming of chronic myeloid leukemia (CML) cells showed epigenetic background-specific oncogenic addiction. (2) Re-differentiation of cancer cell-derived iPSC can recapitulate the progression of human cancer development. PanIN, pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma. (3) Cancer cell heterogeneity can be controlled by the reprogramming of cancer cells.

Figure 3

Generation of human pediatric cancer-like tumors in vivo. An in vivo reprogramming system was established with Dox-inducible alleles for reprogramming factors. Premature termination of in vivo reprogramming in mice causes cancer development consistent with human pediatric cancers (Wilm’s tumor-like tumor in the kidney, hepatoblastoma-like tumor in the liver and pancreatoblastoma-like tumor in the pancreas).

Figure 4

Proof of concept for epigenetics-driven cancer development. In vivo reprogramming results in teratoma formation, whereas premature termination of the reprogramming leads to pediatric cancer-like tumors. The tumor cells can be reprogrammed into iPSC that can be used to generate adult chimeric mice. Note that tumor-derived iPSC in this model give rise to non-neoplastic cells in the chimeric mice.