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Defining the molecular mechanisms of breast cancer metastasis dormancy

Kay Yeung

Appointment Period: 2016-2017, Grant Year: [30]

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Breast Cancer patients can develop metastases from dormant tumor cells years after successful primary tumor resection and treatment. Despite the clinical significance of metastatic latency, the cellular and molecular events regulating dormancy remains largely unknown.

Epithelial-Mesenchymal-Transition (EMT) program plays an important role in promoting tumor cell dissemination and chemoresistance. To understand the dynamic role of EMT during tumor metastasis, my group has established an inducible EMT mouse model where the EMT-inducing transcription factor Twist1 can be induced in a spatiotemporal fashion. Using this model, we showed that activation of Twist1 is 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 is essential for disseminated tumor cells to regain proliferation and form metastases. Together with studies showing that disseminated tumor cells in patient bone marrow present molecular features of EMT, these results raise the possibility that the inability of disseminated tumor cells to revert EMT and regain proliferation could contribute to metastasis dormancy.

To test this hypothesis, we developed an inducible Twist1 mouse breast tumor metastasis model in which Her2-driven breast tumor cells are also labeled with the tdTomato fluorescent protein. We have found that disseminated tumor cells could remain dormant for at least three months in the lung. Using this new model, I plan to test two specific aims.

  1. To characterize dormant tumor cells and their residing niches. I plan to trace and characterize disseminated dormant breast tumor cells in distant organs, including the bone marrow, the lung, the liver, and the brain. The goal of this aim to determine the residing niche of dormant tumor cells in vivo and to characterize their growth and EMT properties.
  1. To determine how tumor dormancy is maintained and regulated in vivo. In this aim, I plan to understand whether the EMT program provides dormant tumor cells with cancer stem cell properties and whether reversion of EMT is an essential step for resurrection from dormancy. Furthermore, one long-standing hypothesis in tumor dormancy is that dormant tumor cells are resistant to chemotherapy-induced cell death. Given that the EMT program has been shown to confer chemoresistance, I will test whether the EMT program provides dormant tumor cells with resistance against chemotherapy in vivo.

The ultimate goal of this study is to advance our understanding of tumor dormancy in connection with EMT in order to lay the scientific foundation for potential new therapies targeting dormant tumor cells.

PUBLICATIONS (resulting from this training)

Trainee recently appointed to grant: publications are still in progress.