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Understanding of colon cancer development via single-cell expression analyses
Recently, gene expression analyses at the single-cell level have become a potent method for investigating cancer heterogeneity or cancer stem cells that presumably constitute a minor fraction of cancer tissues. Such analyses have revealed the distinct cellular compositions of tumors and normal tissues. In order to elucidate generation and progression of refractory solid cancers, we are analyzing gene expression of cancer tissues derived from colorectal and ovarian cancer at single-cell levels.
To examine the dynamic alterations in stem cell-related subpopulations of epithelial cells during colon carcinogenesis, we performed single-cell multiple qPCR analyses using a dextran sulfate sodium (DSS)-induced colon cancer model in ApcMin/+ mice, and identified a subset of Lgr5-positive stem cells that emerged during colon tumorigenesis. These tumor-specific Lgr5-positive cells expressed increased levels of a specific subset of Wnt targets, and showed enhanced tumorigenicity. Among the Wnt targets that were specifically expressed, the long isoform of Tcf1 was required for the proliferation of tumor organoids and drove a unique Wnt target gene expression profile, underscoring the importance of the induction of Tcf1 expression in generating tumorigenic colon stem cells (Shiokawa et al., Cell Reports, 2017; Shiokawa et al, Mol. Cell. Oncol, in press).
We are expanding these observations by performing more comprehensive gene expression analyses. In addition, similar single-cell analyses have been performed on patient-derived xenograft tumors generated after inoculation of in-vitro cultivated colon/ovarian CSCs into immuno-deficient mice.