Dissecting molecular determinants of carcinoma dormancy in vivo

描述（由申请人提供）：癌症患者可以在原发肿瘤切除数年后从休眠的肿瘤细胞发生转移。由于在目前的小鼠肿瘤模型和人类癌症患者中检测远端器官中的单个休眠肿瘤细胞在技术上具有挑战性，因此对调节肿瘤休眠的细胞和分子事件仍然知之甚少。一个被称为上皮-间质转化（Epithelial-Mesenchymal Transition， EMT）的发育过程与单个癌细胞的传播有关。通过表达EMT诱导转录因子Twist1的小鼠肿瘤模型，我们发现Twist1的激活足以促进癌细胞进行EMT并传播到血液循环中。重要的是，在遥远的地点，关闭Twist1以允许EMT的恢复

DESCRIPTION (provided by applicant): Cancer patients can develop metastases from dormant tumor cells years after primary tumor resection. Because it is technically challenging to detect single dormant tumor cells in distant organs in current mouse tumor models and in human cancer patients, it remains largely unknown what cellular and molecular events regulate tumor dormancy. A developmental program termed Epithelial-Mesenchymal Transition (EMT) has been implicated in giving rise to the dissemination of single carcinoma cells. Using a mouse tumor model that express an EMT-inducing transcription factor Twist1, we showed that activation of Twist1 was sufficient to promote carcinoma cells to undergo EMT and disseminate into blood circulation. Importantly, in distant sites, turning off Twist1 to allow reversion of EMT was essential for disseminated tumor cells to regain proliferation and form metastases. In contrast, continuous expression of Twist1 in disseminated tumor cells inhibited metastasis formation in distant organs. Our study raises the possibility that tumor dormancy could be due to the inability of disseminated tumor cells to revert EMT and regain proliferation. In this proposal, we aim to establish a tractable breast tumor mouse model to allow labeling and detection of single dormant tumor cells in vivo and to understand how tumor dormancy is regulated. Our specific aims are 1) to establish a tractable breast tumor metastasis mouse model and characterize dormant tumor cells and their residing niche; 2) to elucidate how tumor dormancy is maintained and regulated in vivo.