Project 433856

The oral cavity is a unique environment that combines complex bacterial biofilms, saliva and fine-balanced mechanisms of innate and cellular immunity. Numerous conditions that manifest in the oral cavity, including potentially malignant oral dysplasia and lichen planus, can promote TNFa-mediated chronic inflammatory states. We hypothesize that the increase in oral TNFa seen in these conditions may directly affect oral epithelial cells and promote malignant transformation which is characterized by invasion into the surrounding tissues. Our laboratory has previously shown that TNFa receptor 1 (TNFR1) is involved in the formation of invasive structures that facilitate cell invasion (invadopodia) which is a critical step in malignant transformation. The specific pathway downstream of TNFR1 activation that promotes malignant transformation in oral epithelial cells is unknown and is the focus of this application. We will combine oral cancer animal models (Objective 1), cellular/molecular biology and patient samples to determine the specific mechanisms linking TNFa-TNFR1 activation to malignant transformation (Objective 2) and whether components of this pathway can be used to identify lesions that have a higher risk of transforming to cancer (Objective 3). In our first objective, we will use an oral cancer mouse model in animals lacking the expression of TNFR1 to determine the role of TNFR1 in oral malignant transformation. In Objective 2 we will define the signaling cascade from TNFR1 activation to invadopodia formation and cell invasion using specific TNFR1 mutants. In our last objective, we will evaluate the expression of members of the pathway described in Objective 2 (e.g. TNFa/TNFR1, invadopodia markers) in oral biopsy samples of potentially malignant lesions and correlate expression with malignant transformation. This application focuses on a novel mechanism that has the potential to change the diagnosis, prognostication, and management of oral premalignant lesions.