Abstract 1628: Early events in metastatic spread: new approaches using targeted therapeutics to disrupt formation of the pre-metastatic niche and development of lung metastases

Abstract

Abstract Solid tumors release soluble factors causing migration of a subset of normal bone marrow derived cells (BMDCs) - primarily VEGFR-1+ hematopoietic progenitor cells and VEGFR-2+ circulating endothelial progenitor cells - from the bone marrow to organ sites. These normal BMDCs self-assemble into a pre-metastatic niche- a micro-environment eventually hosting migratory tumor cells from the primary site. Disruption of this niche or selective targeting the migratory tumor cells may inhibit metastatic spread. The significance and specific characteristics of the BMDCs is still unclear. We have previously observed migration of VEGFR-1+ BMDCs to the lung and lymph nodes, and VEGFR-2+ BMDCs to liver, lung and lymph nodes. Using GFP+ BMDC’s from genetically engineered mice, we characterized the role that recruitment of BMDCs may play in breast cancer metastasis. We assessed the BMDC recruitment profile in lethally irradiated female nu/nu mice transplanted with GFP+ BMDCs from donor mice, followed by orthotopic placement of MDA-MB-231/luc cells or injected with MDA-MB-231/luc conditioned media for 30 days. Flow cytometry results show a gradual increase in the recruitment of CD11b+VEGFR-1+ cells in all the tissues examined from tumor-bearing mice. Recruitment of these cells to the liver in mice treated only with MDA-MB-231/Luc conditioned media was also apparent, but the increase was not as high as in livers of mice with the orthotopically-placed tumors. Recruitment of CD11b+VEGFR-2+ BMDCs was also observed but only in liver and lung. Interestingly, conditioned media seemed to recruit this subset of cells more strongly to these two tissues than signaling from orthotopic tumors. Spleen and lymph node showed minimal recruitment of CD11b+VEGFR-2+ BMDCs. We have previously developed the GrB/VEGF fusion construct- a novel pro-apoptotic fusion protein which specifically targets cells harboring VEGFR2 and have utilized this agent to specifically target BMDCs which are VEGFR2 +. Our preliminary data indicate that treatment with GrB/VEGF does not significantly alter the recruitment of VEGFR-1+ or VEFGR-2+ cells to lungs, when assessed two weeks after the final treatment. We observed increased recruitment of F4/80+ macrophages to the lung. On the other hand, CD11b+Gr-1- BMDCs were significantly reduced following GrB/VEGF treatment, although the F4/80+ subpopulation carrying this signature increased. Studies are ongoing to determine whether systemic administration of this agent can disrupt the formation of the niche and the eventual establishment of metastatic tumors. Understanding the role of BMDCs in metastatic spread and the formation of the pre-metastatic niche and their role in the early development of metastasis will be critical in designing targeted therapeutic approaches to inhibit the metastatic process. Research sponsored, in part, by the Clayton Foundation for Research. Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Michael G. Rosenblum. Early events in metastatic spread: new approaches using targeted therapeutics to disrupt formation of the pre-metastatic niche and development of lung metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1628. doi:10.1158/1538-7445.AM2017-1628