Exploring the role of DAB2 in the blockage of tumor cell-platelet interaction and cancer metastasis

For the advanced stage cancer, metastasis-mediated multi-organs lesions cause morbidity that includes bone pain, immobility, hematopoietic compromises, and spinal cord compression. Understanding the process of how cancer cells outgrow and escape from the primary site is important for development of novel therapeutic approach. In this regards, tumor cell-platelet interaction and beta3 integrin activation have been shown to play a critical role for metastatic cells to colonize distant target organs. We have shown recently that the adapter protein Disabled-2 (DAB2) is a negative regulator of alphaIIb beta3-mediated fibrinogen adhesion and cell signaling. DAB2 expresses abundantly in platelet and is released from platelet as a circulated protein in bloodstream. The extracellular form of DAB2 inhibits platelet aggregation as well as platelet adhesion to the extracellular matrix fibrinogen. On the other hand, DAB2 is a tumor suppressor that is down-regulated in many cancer types, including prostate, breast, ovarian, endocervical adenocarcinomas, colorectal, and pancreatic cancers. Several studies suggest that DAB2 loss can be a critical factor for cancer cell metastasis. Despite prudent evidence to link DAB2 loss with metastasis, little is known whether and how down-regulation of DAB2 in cancer cells is involved in cancer progression and metastasis. In this three year proposal, we will address the function and mechanisms of DAB2 in cancer cell-platelet interaction and metastasis, by integrating the expertise of Dr. Ching-Ping Tseng, a molecular and cellular biologist focusing on elucidating the function of DAB2; of Dr. Chang-Hui Liao, a pharmacologist interested in the platelet physiology and the effect of drugs in platelet activation; of Dr. Kowit-Yu Chong, a stem cell biologist focusing on applying genetic modification approaches in the alteration of embryonic stem cells and generation of transgenic animals. We plan to elucidate the effects and the molecular mechanisms of DAB2 loss on integrin alphaIIb beta3 activity, tumor cell-platelet interaction and metastasis, to investigate the functional role of platelet DAB2 on tumor cells-platelet interaction and the downstream signaling, and to evaluate in vivo function of platelet DAB2 on cancer cell metastasis potential. The completion of this work will contribute to our understanding of the molecular association of DAB2 down-regulation in cancer and the metastatic potential of cancer cells, and thus identify new strategies for blockage of cancer metastasis.

Project ID:PG9704-0320
External Project ID:NHRI-EX97-9612BI