Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy
Patrick Carlson, Arko Dasgupta, Candice A. Grzelak, Jeanna Kim, Alexander Barrett, Ilsa M. Coleman, Ryann E. Shor, Erica T. Goddard, Jinxiang Dai, Emma M. Schweitzer, Andrea R. Lim, Sarah B. Crist, David A. Cheresh, Peter S. Nelson, Kirk C. Hansen, Cyrus M. GhajarNature Cell Biology2019
The presence of disseminated tumour cells (DTCs) in bone marrow is predictive of poor metastasis-free survival of patients with breast cancer with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant che- motherapy. Many assume that this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs protects them from chemotherapy, independent of cell cycle status. We show that chemoresistant DTCs occupy the perivascular niche (PVN) of distant tissues, where they are protected from therapy by vascu- lar endothelium. Inhibiting integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand factor and vascular cell adhesion molecule 1, sensitizes DTCs to chemotherapy. Importantly, chemosensitization is achieved without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities, and ultimately results in pre- vention of bone metastasis. This suggests that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.