Mechanisms of the switch of stem cells to cancer stem cells in head and neck cancer

We have previously discovered that in human and mouse head and neck cancers, Wnt/β-catenin and Bmp signaling are deregulated, and normal stem cells transform to cancer stem cells. Pluripotency genes are upregulated in the cancer stem cells, self-renewal is increased, and the chromatin converts to a permissive state by increased H3K4 trimethylation. If Wnt/β-catenin signaling is chemically blocked in sphere culture, the cancer stem cells differentiate into glandular structures, and this is pre-vented by HDAC and DNMT inhibitors. In the present research, we want to use our attractive threedi-mensional culture system to identify essential genes that control the switch beetween self-renewal and differentiation of cancer stem cells. These experiments involve deep sequencing, chromatinimmuno-precipitation (ChIP) and micro RNA analyses to identify these genes. Candidate genes will then be functionally examined by siRNA knockdown or overexpression in sphere culture, and by mouse genet-ics.The failure to specifically target cancer stem cells is a major hurdle in current tumor therapy. The iden-tification of a gene signature that controls the formation and maintenance of head and neck cancer stem cells, a major tumor type in humans, represents a first step to safely eradicate cancer stem cells in the future.

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