An organ on-a-chip model of oral cancer and bone invasion - ABSTRACT Head and neck squamous cell carcinoma is the sixth most common cancer worldwide with approximately 600,000 new cases diagnosed each year. Oral squamous cell carcinoma (OSCC) in particular, poses a significant health challenge due to its high prevalence and aggressive nature due to its propensity to invade bone. Therefore, elucidating mechanisms of bone OSCC growth and invasion that results in bone destruction is an urgent need in craniofacial and dental research. The calcified bone matrix and cells in the bone microenvironment make up a complex puzzle of variables that have been recognized to play important roles in the progression of oral squamous cell carcinoma towards bone invasion. This is especially due to the lack of in-vitro models that allow for a validated representation of these complex interactions as they happen in humans, in a manipulatable and systematic manner, which have remained virtually non-existent thus far. We have generated a tumor-bone interface on-a-chip model that includes all the players within the bone microenvironment, including mineralized matrix, osteoblasts, osteoclasts and the cells composing the bone vasculature. This system is highly manipulable, allowing for addition or deletion of the cell and matrix variables at play, which offer a unique opportunity to elucidate cause- effect relationships in oral cancer invasion into bone, and to validate next generation models of oral cancer. Here we propose the overarching hypothesis that (1) the reciprocal interactions between OSCC with bone, especially those mediated by osteocytes, regulate the process of oral cancer invasion and destruction of bone tissue, and (2) that our organ-on-a-chip model can replicate these interactions in a controllable, manipulable and validated manner. To address this hypothesis, we propose to (Aim 1) systematically manipulate, characterize and validate tissue microenvironment variables that have been linked to OSCC-bone invasion, (Aim 2) to elucidate and validate the biological mechanisms associated with these events in comparison to clinical samples, and (Aim 3) to test our system as a high-fidelity model to screen therapeutic effects targeting invasive OSCC. To ensure our model's clinical relevance and applicability, we will conduct rigorous validation through in- depth comparisons with clinical samples, assessing molecular signatures, histopathology, and therapeutic responses side- by-side. Our system represents a unique tool for academic researchers, pharma and regulatory bodies to assess drug efficacy and safety in a highly manipulable, high-fidelity human model for OSCC in bone.
