|Thu, Mar 14, 2013||11:00 AM-12:00 PM|
Location: Whitaker 1103
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Regulation of Tumor Dormancy by the Perivascular Niche
Cyrus M. Ghajar, PhD
Lawrence Berkeley National Laboratory, Life Sciences Division
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant in the interim, and what ‘wakes them up’, are fundamental questions of tumor biology. To address these questions, we adopted a multi-disciplinary approach incorporating murine models of human breast cancer dissemination and engineered tumor microenvironments. Metastasis assays in mice revealed that dormant DTCs reside upon the microvasculature of lung, bone marrow (BoMa), and brain. To determine whether this association reflected functional interactions, we engineered organotypic models of lung and BoMa microvascular niches in which breast cancer cells (BCCs) could be tracked long-term. Whereas lung and BoMa stroma each promoted rampant outgrowth of sparsely seeded BCCs, lung and BoMa microvascular niches restrained BCC outgrowth and induced sustained quiescence of up to 90% of resultant tumor cell clusters. To identify endothelial-derived (angiocrine) factors mediating this effect, we performed comparative tandem mass spectrometry on extracellular matrix from decellularized stroma and decellularized microvascular niches. This approach revealed a number of potential angiocrine regulators of DTC dormancy, and a combination of gain- and loss-of-function studies identified one such mediator. Our experiments suggested also that suppressive angiocrine cues are downregulated in endothelial tip cells, and time-lapse analysis showed that sprouting neovasculature does not just permit, but accelerates BCC growth. We confirmed this surprising result in culture and in animal models, and utilized comparative mass spectrometry in combination with gain-of-function studies to identify endothelial tip cell-derived factors that promote tumor growth. In sum, this work provides the first cellular and molecular definition of the ‘dormant niche,’ and identifies also a mechanism by which it can be disrupted. Developing a more complete understanding of the biochemical and physical factors comprising the dormant niche should guide the formulation of therapeutic regimens that either eradicate dormant DTCs, or render them dormant indefinitely.
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