Abstract BS2-2: The perivascular niche protects dormant disseminated tumor cells from therapy

Abstract

Abstract 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, and what wakes them up, are fundamental problems in tumor biology. To address these questions, we use metastasis assays in mice and zebrafish and have determined that the perivascular niche of distant sites like the lung, bone marrow and brain regulate DTC dormancy. We have developed organotypic microvascular niches to specify that endothelial cells regulate breast cancer cell growth, and applied proteomics to identify endothelial-derived mediators of DTC dormancy. More recently, we have begun to explore whether the perivascular niche confers therapeutic resistance to DTCs. I will present data that suggests strongly that the perivascular niche regulates therapeutic resistance of DTCs in a manner that is independent from its role in regulating DTC growth. We have uncovered mediators of perivascular signaling that, when targeted, cause dormant DTCs to respond robustly to chemotherapy. Critically, inhibiting these mediators causes chemosensitization without inducing dormant DTCs to re-enter the cell cycle. We are currently testing this treatment paradigm in pre-clinical models to determine the efficacy in killing dormant DTCs through this approach. I will discuss pre-clinical trial design and important caveats to accurately gauging whether eradication of dormant DTCs significantly prolongs metastasis-free survival. Citation Format: Ghajar CM. The perivascular niche protects dormant disseminated tumor cells from therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS2-2.