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信号被解除调控，正常干细胞转变为癌症干细胞。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H3K4三甲基化转化为允许状态。如果Wnt/β-catenin信号在球培养中被化学阻断，癌症干细胞就会分化成腺状结构，而HDAC和DNMT抑制剂可以阻止这种分化。在目前的研究中，我们希望利用我们有吸引力的三维培养系统来识别控制癌症干细胞自我更新和分化之间转换的必要基因。这些实验包括深度测序，染色质免疫沉淀（ChIP）和微RNA分析来鉴定这些基因。然后，候选基因将通过siRNA敲低或球培养中的过表达以及小鼠遗传学来进行功能检查。无法特异性靶向肿瘤干细胞是目前肿瘤治疗的主要障碍。头颈癌干细胞是人类的一种主要肿瘤类型，控制其形成和维持的基因标志的发现，代表着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.