Project Summary: Resistance to treatment has been a vexing challenge for oral squamous cell carcinoma (OSCC). Within the tumor microenvironment, OSCC cells rapidly expend oxygen and nutrients supplied by the local vasculature. Although hypoxia may inhibit new cell division or increase cell death, those cells most capable of adapting to hypoxia and hypoglycemia may have a selective advantage leading to increased malignant behavior. Indeed, studies have demonstrated a relationship between tumor hypoxia and increased resistance to radiation therapy and chemotherapy. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric transcription factor that plays an essential role in regulating oxygen homeostasis. Expression and activity of the HIF-1 a subunit is influenced by cellular oxygen concentration, as well as numerous growth factors and signaling pathways. Over 70 HIF-1 target genes have been identified that are crucial for angiogenesis, glycolysis and other adaptive mechanisms. Increased HIF-1 expression within oropharyngeal tumors is correlated with worse patient prognosis. This research project is focused upon the role of HIF-1 in modulating OSCC invasion and metastasis. In Specific Aim 1, we will elucidate the function of HIF-1 in OSCC invasion and metastasis. We will characterize the contribution of HIF-1 to the regulation of candidate genes that mediate invasion and metastasis in OSCC in Specific Aim 2. Understanding the biochemical and molecular basis for the altered regulation of HIF-1 in OSCC could lead to opportunities for new therapeutic interventions to limit OSCC invasion and metastasis and improve patient survival. The candidate is a head and neck oncologic surgeon with a research background in signal transduction and head and neck cancer. His career goal is to translate advances in the understanding of OSCC metastasis and invasion into novel and effective therapeutic interventions for head and neck cancer patients. His institution is committed to this goal and has provided the necessary space, protected time and resources. He has assembled a team of mentors and consultants who will not only provide extensive scientific guidance, but also foster his development as an independent investigator. Relevance: Morbidity and mortality due to head and neck cancers is often related to tumor spread by local invasion and distant metastasis. Understanding the role of HIF-1 in OSCC invasion and metastasis may identify new targets for the development of diagnostic biomarkers and therapies designed to monitor and prevent tumor spread. These studies will directly benefit patients with head and neck cancer and may provide valuable insight into the regulation of tumor spread in other types of cancer.