The purpose of this Mentored Clinical Scientist Development Award application is to provide me with the necessary training to develop into an independent investigator of tumor biology. My career goal is to investigate the mechanisms of tumor cell invasion in tumors of the head and neck, and to apply those discoveries to the development of novel therapies designed to inhibit local and distant tumor cell extravasation. The underlying hypothesis of this Mentored Award is that tumor-stromal interactions create a tumor microenvironment that facilitates tumor cell invasion. This application proposes to investigate the role of extracellular matrix metalloproteinase inducer (EMMPRIN) in head and neck squamous cell carcinoma (HNSCC) as a paradigm for understanding the role of tumor-stromal interactions in tumor cell invasion. We hypothesize that tumor-stromal interactions promote HNSCC tumor cell invasion and, specifically that cell surface EMMPRIN expression promotes local tumor cell invasion in tumors of the head and neck by inducing the expression of matrix metalloproteases (MMPs). Recently it has been shown that carcinoma associated fibroblasts undergo distinct cellular alterations compared to normal fibroblasts and secrete most of the peritumoral MMPs. We therefore propose to: 1) localize EMMPRIN and MMP expression in human HNSCC tumors, 2) assess MMP expression in normal and carcinoma associated fibroblasts stimulated by EMMPRIN, 3) determine the in vitro and in vivo phenotype of EMMPRIN upregulation in tumor cell lines, and 4) identify other candidate genes in carcinoma associated fibroblasts that may be important in tumor-stromal interactions. The mentors on this training proposal are international experts in tumor biology and tumor cell invasion. The program is fully endorsed by the Division of Otolaryngology and Department of Surgery, which will provide the necessary resources. I intend to devote my career to: 1) investigating the proteolytic mechanisms of tumor cell invasion and metastasis, 2) understanding the role of the tumor microenvironment in promoting tumor cell growth and metastasis, and 3) bringing new therapies directed at arresting tumor cell invasion into clinical use.
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