NCK1通过调节侵袭性伪足形成影响乳腺癌进展的机制研究

肿瘤是遗传异质性疾病。在肿瘤多阶段演进的过程中，肿瘤细胞播散是最具危险性的过程，其中侵袭性伪足的形成赋予了肿瘤细胞局部侵袭能力。不同肿瘤发生转移的能力不同，乳腺癌的预后和生存与肿瘤转移显著相关。我们从非BRCA1/2乳腺癌家系全外显子组数据中，鉴定出新候选基因NCK1。我们发现NCK1在Basal样乳腺癌中特异高表达，并与肿瘤的转移显著相关。我们所鉴定出的突变位于NCK1别构激活侵袭性伪足形成核心成员N-WASP的基序之中。已有的结果显示，在低侵袭性乳腺癌细胞系MCF7中稳定过表达NCK1突变体，可以促进细胞的增殖和侵袭。我们推测NCK1可能参与调控肿瘤的侵袭性伪足形成继而影响肿瘤的转移。通过整合泛癌数据、体外功能实验、动物实验及临床样本数据，挖掘侵袭性伪足形成所依赖的肿瘤基因背景，阐释NCK1在侵袭性伪足形成中的作用机制，从而为高侵袭性乳腺癌提供潜在的治疗靶点。

Tumors are genetically heterogeneous diseases. During the evolution of tumors, the spread of tumor cells is the most dangerous. The formation of invadopodia endows tumor cells with invasive features and plays a vital role in tumor metastasis. The capability of metastasis varies across different tumor types and the prognosis and survival of breast cancer are significantly related to tumor metastasis. Recently, we identified a candidate cancer gene NCK1 from whole exome sequencing datasets of a non-BRCA1/2 breast cancer pedigree. We found that NCK1 specifically overexpressed in Basal-like breast cancer and was significantly associated with tumor metastasis. The mutation we identified from the breast cancer pedigree located in motif that could activate N-WASP, which was another core factor in invadopodia formation. We observed that overexpression of NCK1 mutant in cell line MCF7, which is low invasive, could promote cell proliferation and invasion. We speculate that NCK1 may involve in regulating the formation of invadopodia, which in turn affects tumor progression and metastasis. By integrating pan-cancer datasets, functional and animal experiments, and clinical sample data, the role of NCK1 and the underlying genetic context in the regulating invadopodia formation could be explained. Depends on that we could provide new candidate therapeutic targets for highly invasive breast cancer patients.