失巢凋亡抵抗和细胞自噬途径的变异是肺癌细胞获得转移的两个重要特性，其维持的分子机制不清楚。我们已证实信号衔接蛋白p66Shc通过激活RhoA，抑制k-Ras活性介导失巢凋亡，在实验动物水平抑制肺癌细胞转移；在研究p66Shc调控EMT过程中我们发现p66Shc与RhoGEF LARG相互作用调控细胞自噬途径，并且肺癌临床样品中p66Shc表达缺失显著影响患者存活，提示作为关键调控蛋白p66Shc介导细胞失巢凋亡和细胞自噬性死亡途径。本课题期望在现有的实验基础上来阐明肺癌细胞在转移过程中p66Shc协调失巢凋亡和细胞自噬性死亡新的调控和维持机制，依据实验结果描绘p66Shc调控失巢凋亡和细胞自噬性死亡的信号途径，并在临床肺癌组织样品中加以验证，同时探讨基于p66Shc生物学效应而进行的抑制肺癌细胞转移治疗的可行性。研究结果将有助于了解肺癌细胞发生发展的调控途径，丰富对肺癌转移分子机制的认识。

Anoikis (detachment-induced apoptosis) resistance and aberrant autophagy (or macroautophagy), which are two main characteristics of lung cancer cells, promote the survival and give rise to metastasis. However, the mechanisms of anoikis and autophagy regulation in cancer cells which sustain oncogenic alterations remain largely elusive. We have previously shown that the adaptor protein p66Shc is a focal adhesion-associated protein and mediates anoikis through a RhoA-dependent mechanosensory test, thus plays an important role in preventing solid cancer metastasis via k-Ras-dependent control of proliferation and survival. In our on-going project of p66Shc function during epithelial-to-mesenchymal transition, EMT, we also identified the interaction between p66Shc and the leukemia-associated RhoGEF, LARG. This interaction may regulate the downstream activation of RhoA. Along with our preliminary data demonstrating that p66Shc significantly correlates with lung cancer patients' survival time, we propose here that reactivation of p66Shc and enhanced autophagy pathway might be a promising strategy to inhibit lung cancer metastasis. To test this hypothesis, we will use clinical lung cancer samples, lung cancer cell lines as well as mouse model to investigate the crosstalk between anoikis resistance and autophagy pathways mediated by p66Shc in vitro and in vivo. Based on our experimental data, the regulatory pathways of anoikis resistance and autophagic cell death will be elucidated and evaluated in clinical lung cancer samples as new candidates for metastasis treatment. Hopefully we may gain significant insight into the anoikis resistance and autophagy-related molecular events associated with lung cancer metastasis and add to means of assessing reactivation of p66Shc and enhanced autophagy for prevention of lung cancer metastasis. Also, a better understanding the role of p66Shc underlying anoikis and autophagic cell death including the determination of the upstream regulators and downstream effectors of p66Shc functional pathways may lead to the development of novel anti-tumor strategies for metastasis.