Dissecting molecular determinants of carcinoma dormancy in vivo

描述（由申请人提供）：癌症患者在原发性肿瘤切除术后数年可从休眠肿瘤细胞发生转移。由于在目前的小鼠肿瘤模型和人类癌症患者中检测远处器官中的单个休眠肿瘤细胞在技术上具有挑战性，因此在很大程度上仍然不知道是什么细胞和分子事件调节肿瘤休眠。称为上皮-间充质转化（EMT）的发育程序涉及引起单个癌细胞的扩散。使用表达EMT诱导转录因子Twist 1的小鼠肿瘤模型，我们发现Twist 1的激活足以促进癌细胞进行EMT并扩散到血液循环中。重要的是，在遥远的站点，关闭Twist 1以允许EMT逆转 对于播散的肿瘤细胞恢复增殖和形成转移是必需的。相反，Twist 1在播散性肿瘤细胞中的持续表达抑制了远处器官的转移形成。我们的研究提出了肿瘤休眠可能是由于播散的肿瘤细胞无法逆转EMT和恢复增殖的可能性。在这一提议中， 我们的目标是建立一个易于处理的乳腺肿瘤小鼠模型，以允许标记和检测体内单个休眠肿瘤细胞，并了解肿瘤休眠是如何调节的。我们的具体目标是：1）建立一个易于处理的乳腺癌转移小鼠模型，并表征休眠的肿瘤细胞及其驻留的生态位; 2）阐明肿瘤休眠是如何在体内维持和调节的。

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.