肿瘤干细胞在头颈癌放疗、化疗耐受和癌症转移过程中发挥了重要作用，探索肿瘤干细胞作用机制有利于提高头颈癌治疗效果和预后。申请人前期研究发现CD10高表达与头颈癌患者预后相关，CD10阳性细胞分泌更多炎症因子，且伴随Hedgehog通路异常激活，生信分析提示CD10与PI3K通路关系密切。我们因此提出假设：CD10异常激活头颈癌中PI3K通路，通过转录因子Gli1介导IL-8分泌，IL-8与CXCR1/2结合进一步激活PI3K通路，藉此增强肿瘤细胞化疗耐受及转移能力。为验证假说，拟首先研究PDX小鼠模型中CD10阳性肿瘤细胞的干细胞生物学行为特征；探索CD10对PI3K-Gli1-IL8信号通路的调控机制；最后利用转基因小鼠模型验证以上机制，探索新的治疗靶点。本研究可进一步阐明CD10对头颈癌化疗抵抗及转移的作用机制，为头颈癌治疗提供新的靶点。

Head and neck squamous cell carcinoma (HNSCC) is frequently considered as one of the toughest challenges that threaten public health. The HNSCC poor prognosis is often attributed to local recurrence, distant metastasis or radio/chemotherapy resistance. Cancer stem cells (CSCs), as the research frontier of HNSCC, have been recognized as a key promotion factor for HNSCC progression. CD10 has been reported to label CSC in various malignancies, and often presaged poor prognosis. In our previous studies, it has been found that overexpression of CD10 in tumor tissue among HNSCC patients is significantly associated with poor prognosis. CD10+ cells derived from HNSCC tissue could secrete more pro-inflammatory cytokines, such as TNFα, IL6 and IL-8, with abnormal activation of hedgehog signaling, which is close related to CSC stemness. Moreover, the bioinformatics analysis results of HNSCC cases suggested that CD10 was mediated via PI3K pathway. Therefore, we hypothesized that CD10 activates PI3K pathway in HNSCC tumorigenesis, and then mediates the secretion of IL-8 via transcription factor Gli1 activated by PI3K pathway. IL-8 and its receptor CXCR1/2 help induce further activation of PI3K pathway, resulting as the emergence of enhanced chemoresistance and metastasis ability. To verify the above hypothesis, the biological properties of CD10+ cells in PDX mouse model with HNSCC are planned to study firstly; then the regulatory mechanisms of CD10 on PI3K-Gli1-IL8 cascade signaling are explored; finally, the hypothesized mechanisms and novel therapeutic targets of HNSCC will be confirmed using transgenic mouse model. This study could help elucidate the mechanism of HNSCC chemoresistance and metastasis properties mediated by CD10, but also provide a new option for the HNSCC treatment, and a tool for clinical evaluation of HNSCC prognosis.