We have discovered that highly aggressive cancer cells of various types occasionally divide asymmetrically by triggering an mTORC2-AKT1-kinase signaling network late during mitosis to produce one proliferating daughter cell and another daughter that exits the cell cycle into a "G0-like" state. These G0-like cancer cells display striking and complex epigenomic and transcriptional changes, suggesting that cancer cells can undergo a profound epigenomic "switch" in cell state during cell division to become quiescent. Importantly, we have also identified these G0-like cancer cells within human breast tumors where they appear to be highly resistant to combination chemotherapy, suggesting that these cells may contribute significantly to the minimal residual disease that causes disease recurrence after systemic therapy in patients with solid tumors. We now propose extending these intriguing experimental observations through a combination of cutting edge molecular, epigenomic, and computational approaches. We will identify and validate genes that can initiate and / or maintain cancer cell quiescence to deliver novel and highly validated targets for disrupting tumor dormancy in vivo. Our major goal is to use this insight to develop novel cancer drug combinations for patients with a wide variety of tumor types.

Public Health Relevance

We have discovered a new signaling mechanism that triggers asymmetric cancer cell division to produce quiescent cancer cells that are resistant to combination chemotherapy. We now propose using new experimental avenues that we have developed to identify and validate molecular targets that initiate and / or maintain asymmetric cancer cell division and quiescence. The major goal of these studies is to suggest entirely new strategies for targeting dormant cancer cells to aid in the design of more effective cancer drug combinations for patients with a wide variety of tumor types.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-0 (J1))
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Hildesheim, Jeffrey
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Massachusetts General Hospital
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