This five year career development program is specifically tailored for Dr. Tammara Watts to become an expert in head and neck cancer biology and immunology with a specialization in stem cells and the tumor microenvironment, allowing her to transition into an independent, extramurally funded investigator. She has been engaged in translational research since her initial Ph.D. training; since then, she has received her clinical training, is a board-certified otolaryngologist with special training in head and neck oncology, and is now ideally situated to conduct translational research designed to improve the current management of head and neck squamous cell carcinoma (HNSCC). Presently, she enjoys dedicated research time, but needs coursework and support to gain knowledge in the rapidly evolving fields of stem cell biology, cancer biology and immunology, and experience in and funding for the molecular techniques necessary to design and conduct experiments to address the specific aims of this project. Her immediate career goals are to continue her studies characterizing the role of stem cells in the HNSCC microenvironment. To this end, a primary mentoring team comprised of stem cell and HNSCC researchers Drs. Don W. Powell and Jeffrey Myers will oversee her mentored research plan. Didactic coursework is planned in cancer biology, stem cell physiology, immunology, biostatistics, and grant writing. Interactive coaching sessions, through the American Association of Medical Colleges (AAMC) are planned to help prepare her for transitioning into an independent investigator pursuing R-level funding. Her research project focuses on characterizing the paracrine signaling mechanisms underlying the homing of mesenchymal stem cells (MSCs) to the HNSCC tumor microenvironment. Her preliminary data show that MSCs can be identified in the primary tumors of patients and in experimental murine models of HNSCC. She has also shown that HNSCC secretes chemotactic factors that cause migration and invasion of MSCs to the tumor microenvironment. Aim 1 will characterize the stem cell niche in the tumor microenvironment by confocal microscopy, flow cytometry, Western immunoblotting, and migration/invasion assays. The signaling mechanisms used by HNSCC tumor cells for MSC homing will be addressed in Aim 2, using shRNA knockdowns of candidate factors identified in her preliminary data. Finally, Aim 3 will address the consequences of MSCs and other stem cells in the HNSCC tumor microenvironment on tumor growth and metastasis, in vivo. Successful completion of this project will provide a much better understanding of MSC homing to the HNSCC tumor microenvironment and how the presence of MSCs and other stem cells there contributes to chemo-radiation treatment failures in this challenging patient population. To our knowledge there is limited information on the pathophysiology of MSCs in the HNSCC tumor microenvironment in the literature, making this project innovative with the promise of high impact. Long-term, this research project will lay the foundation for Dr. Watts to develop into an independent investigator with R01 funding.