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

我们之前已经发现，在人类和小鼠头颈癌中，Wnt/β-catenin和Bmp信号转导失调，正常干细胞转化为癌症干细胞。多能性基因在癌症干细胞中上调，自我更新增加，并且染色质通过增加的H3 K4三甲基化转化为允许状态。如果Wnt/β-连环蛋白信号传导在球体培养物中被化学阻断，则癌症干细胞分化成腺体结构，并且这被HDAC和DNMT抑制剂阻止。在本研究中，我们希望利用我们有吸引力的三维培养系统来鉴定控制癌症干细胞自我更新和分化之间转换的必需基因。这些实验涉及深度测序，染色质免疫沉淀（ChIP）和microRNA分析，以确定这些基因。然后通过siRNA敲低或在球体培养中过表达以及通过小鼠遗传学对候选基因进行功能性检查。未能特异性靶向癌症干细胞是当前肿瘤治疗的主要障碍。控制头颈癌干细胞（人类主要肿瘤类型）形成和维持的基因签名的验证，代表了未来安全根除癌症干细胞的第一步。

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.