Ezrin-ACAP4-ARF6信号轴应答肿瘤转移前微环境的效应机制研究

肿瘤转移是恶性肿瘤的主要特征，其发生涉及到肿瘤细胞本身的内在因素及其所处转移前微环境的动态变化。肿瘤转移是一个复杂的、多因素调控的动态过程，在分子水平上主要表现为蛋白质复合物的时空动态调控。本项目申请由两个紧密合作的交叉学科团队提出，5年来取得了以“Ezrin磷酸化调控肝癌转移”和“MST-ezrin-ACAP4信号轴调控细胞可塑性”为代表的系列研究成果。合作发表Cancer Res、PNAS等高水平研究论文9篇。本项目拟在综合前期合作的基础上，阐明微环境如何通过MST4-ACAP4分子作用调控肝癌与乳腺癌细胞可塑性，解析ARF6 GTP酶活性在肿瘤细胞应答微环境变化过程中的时空动力学特征，并利用小分子抑制剂MSM0601解析ACAP4在转移前微环境形成、维系与乳腺癌转移的效应机制。本项目的实施将铸造一支国际先进水平的肿瘤微环境科研团队并发掘1-2个干预肿瘤转移的先导化合物。

Metastasis is a life-threaten hallmark of tumor malignance which involves complicated and dynamic interactions between tumors and its surrounding microenvironment. At molecular level, the aforementioned interactions exhibit as spatiotemporal dynamics of context-dependent signaling axis. The proposed studies were jointly put forward by two long-term collaborative research units. This synergistic team has delineated the role of ezrin phosphorylation in liver cancer metastasis and characterized MST4-ezrin-ACAP4 signaling axis. Our collaborative works have appeared in prestigious journals such as Cancer Research and PNAS. Here we plan to consolidate our resource and expertise to delineate how MST4-ACAP4 signaling axis orchestrates tumor-micro-environment interactions in cancer metastasis. In addition, we plan to illustrate the molecular dynamics of ARF6-GTPase gradient in tumor cells in response to micro-environmental factors such as cytokines. Finally, we plan to use our novel ACAP4 inhibitor to probe the precise role of ACAP4 signaling in tumor-micro-environment interactions and tumor cell metastasis in triple negative breast cancer, the most invasive tumor type in breast cancer. The completion of proposed work will build a world-class translational research team centered on tumor-micro-environment interactions and provide l-2 lead compounds for precision interrogation of tumor progression.