Guest Speaker: Dr. Xaralabos (Bob) Varelas

Aging and Tissue Mechanics: How the Aged Microenvironment Shapes Tumor Responses in Head and Neck Cancer

ABSTRACT

Mechanical changes within tissues are increasingly recognized as key regulators of cancer initiation and progression. Aging, in particular, reshapes the biomechanical and cellular landscape of tissues, yet little is known about how such changes affect tumor biology. Our work investigates how age-associated alterations in tissue mechanics influence tumor-immune interactions and cancer cell fate decisions in the context of head & neck cancers, the sixth most prominent cancers worldwide. We find that aging associated collagen-changes in the oral cavity produce a mechanically stiff environment that elicits distinct mechanotransduction in carcinoma cells. These mechanosensitive signals drive a repressed immunogenic transcriptional state, reduces immune infiltration, and enable accelerated tumor growth, phenotypes mirrored in age-associated human head & neck cancers. We show that YAP-TEAD function as key mechanosensitive effectors of the age-associated immunogenic program, and that inhibiting YAP-TEAD signaling restores immune engagement and restricts tumor development in aged animals. Together, these findings reveal how distinct aging-driven mechanical remodeling of the tissue microenvironment directs carcinoma cell phenotypes and shapes tumor immunity.