Mechanical regulation of tumor invasion and immune evasion in head and neck cancer - this F31 predoctoral fellowship proposal aims to provide fatemeh tavakoli joorabi with individualized, mentored…

Mechanical regulation of tumor invasion and immune evasion in head and neck cancer - this F31 predoctoral fellowship proposal aims to provide fatemeh tavakoli joorabi with individualized, mentored research training while conducting biomedical research. The comprehensive training plan is designed to enhance MS. Joorabi's potential for, and commitment to, an independent scientific career, culminating in preparation for a K99/R00 application. Training provides interdisciplinary expertise in mechanobiology, biomaterials engineering, and tumor immunology, including advanced coursework (immunology, DIY transcriptomics), technical skills (spatial transcriptomics, in vivo modeling), and professional development through grant-writing workshops (penn's grant proposal success series) and conferences (aacr, bmes). A multidisciplinary mentoring team spanning engineering, immunology, and clinical oncology provides structured guidance toward research independence. Together, novel research and structured training will equip MS. Joorabi with the skills to transition successfully to the next career stage. Head and neck squamous cell carcinoma (hnscc) remains a major global health challenge, with anti-PD-1 therapies showing modest response rates (13-15%), highlighting the need to uncover mechanisms of immune resistance. This project addresses the poorly defined role of extracellular matrix (ECM) viscoelasticity in shaping tumor-immune behavior. We hypothesize that ECM elasticity (slower stress relaxation) maintains controlled tumor behavior and immune responsiveness, whereas increased viscoelastic relaxation drives invasion and suppresses anti-tumor immunity through the YAP/TAZ-TGF-β axis. Preliminary data using a tunable 3D alginate-collagen hydrogel system that decouples stiffness from viscoelasticity show that fast stress-relaxing (viscous) matrices enhance invasion, activate YAP/TAZ and TGF-β signaling, and promote immune evasion by reducing MHC-i and elevating PD-L1. Viscous conditions also push t cells toward an exhausted, less cytotoxic phenotype. Aim 1 will determine whether viscoelastic ECM cues mechanically "educate" hnscc cells toward a durable aggressive state. Aim 1A defines YAP/TAZ and TGF-β roles in invasion; aim 1B tests durability of mechanical education; aim 1C validates persistence in vivo using immunocompetent MOC2 models. Aim 2 examines how mechanical education alters anti-tumor immunity: aim 2A tests effects on antigen presentation; aim 2B assesses t-cell activation and cytotoxicity; aim 2C evaluates in vivo immune infiltration and whether YAP/TAZ or TGF-β inhibition enhances anti-PD-1 responsiveness in viscous-educated tumors. By establishing ECM viscoelasticity as a key, modifiable driver of tumor aggression and anti-PD-1 resistance, this research opens new avenues for mechanically targeted therapies to strengthen immune control in solid tumors.