Abstract 2803: Disabeled-2 (Dab-2) modulates platelet-cancer cell interactions through its sulfatide binding domain

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.2803-2803
• Main Authors: Andreano, Kaitlyn, Fu, Xiangping, Capelluto, Daniel, Finkielstein, Carla
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-2803

Platelets’ role in cancer progression and metastasis has largely been attributed to platelet-mediated enhancement of tumor cell survival, extravasation (exiting form capillaries and entering organs), and angiogenesis. Correlations exist between the ability of some tumor cells to aggregate platelets in vitro and their metastatic potential in vivo that it is manifested as a hypercoagulable state found in most cancer patients. We have identified a tumor suppressor molecule (Dab-2) that it is released upon platelet activation and that modulates the extent of blood clotting. Our results show Dab-2 is released from alpha-granules in the platelet to the membrane surface where specifically binds to the integrin receptor, thus inhibiting platelet aggregation. Binding of Dab-2 to integrins is modulated by sulfatides, a form of glycosphingolipid that accumulate in platelet membrane and effectively compete for Dab-2 levels. Interestingly, we found that the N-terminal region of Dab-2 specifically binds to sulfatides through two conserved sulfatide-binding sites. Upon activation, sulfatides protect Dab-2 from thrombin cleavage, facilitate its internalization and modulate the surface expression of P-selectin, a coagulation protein needed for stabilization of platelet aggregates. P-selectin also mediates both tumor cell adhesion to vascular endothelial cells and the interaction between activated platelets and cancer cells (emboli) during metastasis. Interestingly, our data show that Dab-2/sulfatide recognition influences the stability of platelet aggregates heterotypically with cancer cells through sulfatide binding and, indirectly, by controlling P-selectin levels. Thus, we hypothesize that manipulation of Dab-2 function in response of platelet activation will impact emboli formation offering an alternative route for therapeutic strategies aimed to control metastatic processes. Citation Format: Kaitlyn Andreano, Xiangping Fu, Daniel Capelluto, Carla Finkielstein. Disabeled-2 (Dab-2) modulates platelet-cancer cell interactions through its sulfatide binding domain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2803. doi:10.1158/1538-7445.AM2013-2803