Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFβ signaling.
Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFβ signaling.
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作者：
Du L;Chen X;Cao Y;Lu L;Zhang F;Bornstein S;Li Y;Owens P;Malkoski S;Said S;Jin F;Kulesz-Martin M;Gross N;Wang XJ;Lu SL
头部和颈部鳞状细胞癌（HNSCC）患者的预后较差，侵袭和转移是死亡率的主要原因。与PI3K途径在细胞生长中的作用相比，人类HNSCC中最常见的遗传改变之一肿瘤入侵和转移的PI3K途径尚未很好地描绘出我们生成了PIK3CA基因工程的小鼠模型（PIK3CA-GEMM），其中Wildtype Pik3Ca在头部和颈部上表达不足以启动Hnscc形成。 ，在小鼠口服上皮中的PIK3CA过表达中，它显着提高了肿瘤敏感性。通过增加上皮 - 间质转变并富含肿瘤上皮细胞中的癌症干细胞表型来增加肿瘤的侵入性和转移。但是，分子分析表明，PIK3CA驱动的HNSCC的进展得到PDK1的支持和增强的TGFβ信号而不是通过AKT检查人类HNSCC临床样本，表明PIK3CA和PDK1蛋白水平与肿瘤的进展相关，从而强调了该途径的重要性。提供靶向PI3K/PDK1和TGFβ信号传导的理由放大。
Head and neck squamous cell carcinoma (HNSCC) patients have a poor prognosis, with invasion and metastasis as major causes of mortality. The phosphatidylinositol 3-kinase (PI3K) pathway regulates a wide range of cellular processes crucial for tumorigenesis, and PIK3CA amplification and mutation are among the most common genetic alterations in human HNSCC. Compared to the well-documented roles of the PI3K pathway in cell growth and survival, the roles of the PI3K pathway in tumor invasion and metastasis have not been well delineated. We generated a PIK3CA-genetically engineered mouse model (PIK3CA-GEMM) in which wildtype PIK3CA is overexpressed in head and neck epithelium. Although PIK3CA overexpression alone was not sufficient to initiate HNSCC formation, it significantly increased tumor susceptibility in an oral-carcinogenesis mouse model. PIK3CA overexpression in mouse oral epithelium increased tumor invasiveness and metastasis by increasing epithelial-mesenchymal transition and by enriching a cancer stem cell phenotype in tumor epithelial cells. In addition to these epithelial alterations, we also observed marked inflammation in tumor stroma. AKT is a central signaling mediator of the PI3K pathway. However, molecular analysis suggested that progression of PIK3CA-driven HNSCC is facilitated by PDK1 and enhanced TGFβ signaling rather than by AKT. Examination of human HNSCC clinical samples revealed that both PIK3CA and PDK1 protein levels correlated with tumor progression, highlighting the significance of this pathway. In summary, our results offer significant insight into how PIK3CA-overexpression drives HNSCC invasion and metastasis, providing a rationale for targeting PI3K/PDK1 and TGFβ signaling in advanced HNSCC patients with PIK3CA amplification.