Abstract 5209: Non-tumoral autotaxin stored into platelet α-granules promotes breast cancer cell metastasis

Abstract

Abstract Autotaxin (ATX) through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers and we have shown previously that together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the mechanisms that regulate the pathophysiological significances of the interactions between circulating LPA, ATX, and platelets remain undefined in cancer. Here we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. For this study, we used two human breast cancer cell lines (MDA-MB-231, MDA-B02) that do not express ATX. Our in vitro and in vivo experiments demonstrate that non-tumoral ATX controls the early stage of bone colonization by tumor cells and to a less extent osteolytic bone metastasis progression. Moreover, expression of a dominant negative integrin αvβ3-Δ744 or treatment with the anti human αvβ&;3 monoclonal antibody LM609 completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells and demonstrate the therapeutic potential of disrupting the binding of non-tumor-derived ATX with the tumor cells for the prevention of metastasis. Citation Format: Raphael Leblanc, Sue-Chin Lee, Dereck Norman, Johnny Ribeiro, Gabor Tigyi, Olivier Peyruchaud. Non-tumoral autotaxin stored into platelet α-granules promotes breast cancer cell metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5209. doi:10.1158/1538-7445.AM2015-5209