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Colon CSCs are sensitized by HDACinhibitors in a FOXO-dependent fashion

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If you have a question about this talk, please contact Florian Markowetz.

Cancer Stem Cells (CSC) display selective resistance towards chemotherapy and are thought to be the cause of therapy failure. In this study we explored the underlying mechanisms using a Wnt-reporter construct to identify CSC . We observed that high Wnt activity functionally designates the colon CSC population. Moreover, in primary cancers the tumor cells with high Wnt pathway activity are preferentially localized close to stromal myofibroblasts and derive HGF -dependent signals from the microenvironment. Using an in vitro chemotherapy analysis we observed that CSCs are selectively resistant to chemotherapy. This resistance can be circumvented by pretreatment with HDAC inhibitors, which change the level of pro and anti-apoptotic molecules and thereby facilitate cell death. Importantly, treatment with HDAC inhibitors results in a strong reduction of typical stem cell markers and shows strong induction of differentiation. HDAC inhibitors therefore pose a novel means to sensitize CSC to therapy by enhancing their differentiation. Mechanistic insight into this mechanism and the role of FOXO transcription factors will be presented.

This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.

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