Our knowledge of cancer progression has grown exponentially by our ability to model cancer initiation. Still the major challenge faced by physicians is the prevention and treatment of metastasis, the main reason for cancer related deaths. Our understanding of metastasis has lagged behind that of primary tumor biology resulting in limited metastasis preventive therapies. Our work focuses on understanding the biology of residual cancer cells that persist in a dormant state after initial therapy. This knowledge will allow targeting minimal residual disease before it becomes clinically detectable and thus preventing recurrences. Our research is revealing ways to maintain residual cancer dormancy, kill dormant cancer cells and markers to determine the dormant or active state of disseminated disease.
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Surprisingly, cancer patients presumed cured after primary tumor removal and therapy, can carry non-proliferating ‘dormant’ disseminated tumor cells (DTCs) for years before reactivating to form incurable metastasis. Thus, despite cancer cells carrying genetic alterations micro-environmental and epigenetic mechanisms appear to induce tumor cell dormancy. My lab focuses on understanding the biology of dormant DTCs and their reactivation, to target them and prevent relapse. This contrasts to the vast majority of cancer research, which is aimed at understanding constant cancer growth. My team led a paradigm shift that is revealing novel cancer biology. We integrated mechanisms of basic stress and mitogenic signaling, adult stem cell and micro-environmental biology and discovered that a reciprocal crosstalk between DTCs and the microenvironment regulates the inter-conversion between dormancy and proliferation.

Residual tumor cells (RTCs) after tumor removal enter dormancy in surgery margins. NR2F1 and SOX9 pinpointdormant RTCs.

Overall Impact on the Cancer Research Field: For over 20 years we have focused on understanding the biology of metastasis. Specifically, on the dormant nature of minimal residual disease in cancer. More than two decades ago the concepts and mechanisms of cancer dormancy were rudimentary at best and considered obscure phenomenology. The output of our research program, has changed this notion. By methodically dissecting this biology we have been able to incorporate it as a key hallmark of cancer progression that was overlooked and punctually investigated for many decades. During this time, research on cancer dormancy has gone from being a sporadic mention in major meetings and occasional publications, to now being a central component of major cancer research meetings in the world accompanied by an exponential increase in publications. Major cancer centers in the country and numerous research centers across the world now have programs on cancer dormancy. Our research has helped transformed globally the paradigm of cancer research changing how we study, model and how we will treat cancer. This new paradigm is being exhaustively probed and is helping bring new concepts, data, therapies and diagnostics in cancer.

Dormant HER2+ early disseminated cancer cells (eDCCs) are TWIST1-high. However, DCCs found in lungs of animals with metastatic disease are frequently TWIST1-negative. This switch signals a resumption of proliferation. From Harper and Sosa et al., Nature. 2016 Dec 14. doi: 10.1038/nature20609.
Movie: intravital imaging of MMTV-Her2-CFP mice revealing early dissemination. Nature. (2016) Dec 14. doi: 10.1038/nature20609. [Epub ahead of print] PMID:27974798.