This Proposal describes a 5 year training program for the development of a research career in cancer biology. The principal investigator (Dr. Zijlstra) outlines a plan to use an established base of infrastructure and research support in conjunction with guidance from his mentor (Dr. Quigley) and collaborative interactions with established investigators (Dr. Stuhlmann and Dr. Blancafort) to expand his scientific skills and mediate his transition to an independent career in cancer research. Project Summary: While metastasis to vital organs is lethal, it is an inefficient biological process suitable for therapeutic intervention. The first step towards intervention is the identification of suitable molecular targets and mechanisms. One of the primary requirements of tumor cell dissemination is the ability of the cell to mobilize itself, intravasate, and leave the original tumor site. This application proposes to characterize CD151 controlled mechanism of migration-mediated intravasation, and to identify new molecular targets which regulate migration in vivo. We have demonstrated that a function blocking antibody targeted to CD151 disrupts a mechanism of in vivo tumor cell motility shared by divergent tumor cell lineages. The resulting inhibition of in vivo motility prevents intravasation and halts metastasis. These observations suggest that highly aggressive tumors can be immobilized, that we can thereby prevent their ability to intravasate at the site of the primary tumor and, as a consequence, limit their metastatic ability. This application proposes to investigate the mechanism of migration responsible for intravasation with the use of intravital imaging and our quantitative metastasis model in three specific aims:
Specific aim #1 is to identify the biological mechanism and route of tumor cell intravasation.
Specific aim #2 To elucidate the molecular mechanism by which the tetraspanin CD151 regulates intravasation during metastatic dissemination in vivo.
Specific aim #3 is to use Artificial Transcription Factors (ATFs) in conjunction with positive selection in an in vivo metastasis model in order to identify molecular targets that inhibit tumor cell migration and intravasation. Project Relevance: Metastasis is the primary cause of cancer related deaths. In order to metastasize, tumor cells have mobilize themselves and enter the circulation. The proposed work is focused on identifying and understanding the mechanisms by which tumor cells can be immobilized.
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