Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy

The presence of disseminated tumour cells (DTCs) in bone marrow predicts poorer metastasis-free survival of breast cancer patients with localized disease, and their eradication improves long-term prognosis. DTCs persist in distant tissues despite administration of adjuvant chemotherapy, ostensibly because the majority of DTCs are quiescent. Here, we provide evidence that the microenvironment of DTCs protects them from chemotherapy independent of cell cycle status. We show that chemoresistant DTCs associate with the perivascular niche (PVN) of distant tissues, and that they are protected from therapies by vascular endothelium. Inhibiting key integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand Factor, sensitizes DTCs to chemotherapy and prevents bone metastasis. Importantly, chemosensitization is achieved without inducing DTC proliferation, or exacerbating chemotherapy-induced toxicities. These results suggest that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis. Overall design: RNA sequencing of bone marrow mesenchymal stem cells (MSCs) and bone marrow microvascular niches (MVNs) by RNAseq using Illumina HiSeq 2500.

4

Carlson P, Dasgupta A, Grzelak CA, Kim J, Barrett A, Coleman IM, Shor RE, Goddard ET, Dai J, Schweitzer EM, Lim AR, Crist SB, Cheresh DA, Nelson PS, Hansen KC, Ghajar CM