Dissecting molecular determinants of carcinoma dormancy in vivo

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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.