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Scalable Organotypic Models of Tumor Dormancy

2013-097

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ABSTRACT:

Despite years of research, the five-year survival rate for all cancer types combined is 66.1%, and the ten-year rate is 32% (National Cancer Institute, 2011). Learning how disseminated tumor cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems that must be solved to increase cancer survivor rates over time.

To address this issue, Berkeley Lab researcher Mina Bissell and her team developed dormancy models of lung and bone marrow microvascular niches. These organotypic 3D human co-culture models can be used in conjunction with omics technologies to identify factors that characterize the dormant niche, induce tumor cells into a state of dormancy, or draw them out of this state.

Unlike other dormancy models, the team’s technology induces fully malignant, genotypically aberrant tumor cells into a state of sustained dormancy and recapitulates well in vivo. Models based on the use of cancer cell lines selected for poor growth properties cannot study how the cells are induced into a dormant state. In addition, deducing tumor dormancy through immunohistochemistry staining, statistical risk analysis, and clinicopathological evaluation is difficult and uncertain, potentially leading to over treatment and uncomfortable side effects or under treatment and possible recurrence.

The researchers’ paper, linked below, describes how the team used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. The team then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit but accelerate BCC outgrowth. The researchers confirmed this result in dormancy models and in zebrafish, and identified active TGF-1 and periostin as tumor-promoting factors derived from endothelial tip cells. Their work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.

FOR MORE INFORMATION:

Ghajar, C. M., Peinado, H., Mori, H., Matei, I.R., Evanson, K.J., Brazier, H., Almeida, D., Koller, A., Hajjar, K. A., Stainier, D. Y. R., Chen, E. I., Lyden, D., Bissell, M. J. "The perivascular niche regulates breast tumor dormancy," Nature Cell Biology, Vol. 15, No. 7, July 2013.

STATUS: Patent pending. Available for licensing or collaborative research.

REFERENCE NUMBER: 2013-097

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