线粒体互作网络调控线粒体稳态并参与乳腺癌发生发展的机制研究

乳腺癌是女性发病率最高的恶性肿瘤，其复发、转移和耐药严重威胁患者生命。申请人实验室发现线粒体动态变化在乳腺癌转移过程中起重要作用（Oncogene，2013）；聚焦线粒体蛋白质合成的整合与协调，发现线粒体延伸因子EF4与肿瘤密切相关（Cancer Res，2018）。进一步发现线粒体与内质网互作影响EF4表达；进展期及转移乳腺癌病人肿瘤组织中EF4表达水平明显增加；EF4介导线粒体翻译，并影响乳腺癌细胞的生长与转移。拟在此基础上开展如下研究：①探索线粒体与内质网互作在线粒体蛋白质翻译过程中的重要作用；②解析线粒体与内质网互作通过调控EF4表达、转运及降解，精确协调线粒体呼吸链复合物翻译与组装，影响线粒体生物发生、动态变化、稳态维持及能量代谢的分子机理；③阐明线粒体与内质网互作维持线粒体稳态并参与乳腺癌发生发展及迁移侵袭的关键机制。研究结果将进一步加深对于细胞器互作重要病理生理作用的认识。

Breast cancer is the most common solid cancer and the second leading cause of cancer death in women. Patients who cannot be cured are primarily those in whom breast cancer has metastasized (i.e., migrated and invaded vital organs) and developed resistance to traditional therapies. Understanding the underlying molecular mechanisms that allow cancer cells to acquire metastatic abilities and drug resistance can lead to development of novel therapies. Mitochondria are dynamic organelles that supply energy required for cell survival, proliferation, and migration. Recent studies have implicated that mitochondrial dynamics such as fission and fusion is closly related with the organelle interactome, and is critical for cancer progression and survival. However, it is still unclear how cancer cells modify mitochondrial dynamics to acquire metastatic abilities and resistance to anti-cancer drug-induced apoptosis. The applicant has conducted in-depth research on this topic for many years. Some of our research results have been published in prestige journals such as Cancer Res and Autophagy. More recently, the applicant identified the mitochondrial protein translation elongation factor 4 (EF4) as an important regulator in the development and progression of lung and cervical cancer (Cancer Res, 2018). Interestingly, EF4 expression levels were markedly elevated in breast cancer tissues and overexpression of EF4 significantly altered the dynamic balance of mitochondrial fission/fusion with increased mitochondrial membrane potential and increased rate of aerobic respiration in breast cancer cells. Importantly, breast cancer cells acquired metastatic abilities and resistance to apoptosis-inducing factors following overexpression of EF4. Thus, we hypothesize that aberrantly upregulated EF4 regulates mitochondrial dynamics and functions, which in turn enhances breast cancer cell growth, metastatic abilities and suppresses drug-induced cell apoptosis. We will use molecular, cellular and animal models to test this hypothesis via following three specific aims. Aim 1 will assess the importance of ER-mitochondria interaction in mitochondrial translation. Aim 2 will determine the molecular mechanism for EF4 regulation of mitochondrial fission/fusion homeostasis and functions in breast cancer cells. Aim 3 will dissect the mitochondrial protein synthesis and quality control in breast cancer cells. Successful completion of this research project will identify functional molecules, either EF4 or other new targets in regulation of mitochondrial interaction network, which may allow breast cancer cells to grow and acquire metastatic abilities and drug resistance. Establishing the pathological role of mitochondrial interaction network in cancer growth, metastasis and drug resistance will offer multiple novel drug targets as a first step to address the overarching challenge of developing effective treatments for metastatic and drug-resistant breast cancer.