Project Summary Head and neck cancer squamous cell carcinomas (HNSCC) are the seventh most common cancers globally and are associated with poor survival rates. Pharmacological treatments for HNSCC remain largely ineffective and improving therapies requires the identification of novel factors that modulate not just the tumor but also the surrounding permissive oral microenvironment. Aging is a variable tightly associated with HNSCC development and is linked to tissue alterations and defective immune responses. However, while older chronological age is associated with tumor development and elderly HNSCC patients exhibit worse five-year survival, very little is known about the molecular mechanisms by which aging contributes to the etiology of HNSCC. The goal of this proposal is to define signals associated with HNSCC progression in aged tissues with the hope to uncover targetable mechanisms that may offer new therapeutic avenues. To test the influence of age on HNSCC, we optimized syngeneic orthotopic tongue xenograft models of HNSCC and have observed more rapid tumor growth in old animals, with tumors exhibiting an age-associated, immune evasive and transcriptionally-distinct tumor cell states. We have found that these age-associated alterations correlate with increased extracellular matrix levels that we hypothesize the mechanical properties of old tissues direct distinct mechanosensitive signals. Our observations suggest that the mechanical-effector YAP, a transcriptional regulator mediating Hippo pathway signaling that has pro-tumorigenic functions in HNSCC, is linked to age-associated tumorigenesis. We propose to examine the relationship between aging, extracellular matrix dynamics, YAP activity and YAP-directed functions, including immune evasion. We further plan to compare matrix dynamics and tissue elasticity across mice of different chronological age and test how increasing collagen levels or reducing collagen crosslinking affects tumorigenic behavior. We will further test the consequences of inhibiting YAP activity in age-associated tumors, profiling accompanying transcriptional and cellular changes. Finally, we will test how reintroducing an absent chemokine program regulated by YAP that is repressed in the old tongue microenvironment impacts tumor growth and tumor lymphocyte infiltration. Data collected from our study will provide a comprehensive assessment of age-associated mechanical signals and offer new insight into mechanisms that may direct the heterogenous lymphocytic functions observed in HNSCC.

Project Narrative Head and neck cancers rank among the deadliest and most diagnosed cancers globally. Treatment strategies for head and neck cancers are limited, with emerging therapies, such as cancer immunotherapies, showing promising but heterogeneous responses that are poorly understood. This study focuses on understanding how aging-associated changes in the tumor microenvironment contribute to the immune evasive behavior of oral cancer, with the goal of improving clinical outcomes for patients.