Author ORCID Identifier
Document Type
Dissertation
Date of Award
2025
Degree Name
Doctor of Philosophy (PhD)
Department
Basic Biomedical Science
First Advisor
Paola D Vermeer
Abstract
Head and neck squamous cell carcinomas (HNSCC) are an epithelial cancer prevalent across the world and are divided into two subcategories: human papillomavirus-mediated (HPV+) and carcinogen-mediated (HPV-) HNSCC. These subgroups have distinct patient populations, divergent responses to therapy, and prognoses, however the foundational mechanisms that facilitate these differences are not well understood or defined. Recently, the presence and function of sensory neurons within the tumor environment of various solid tumors has been identified and investigated. Herein, we identify differences in the presence of TRPV1+ sensory neurons and neuron structures in the tumor environment of HPV+ and HPV- HNSCC, correlating with patient prognosis. Genetic factors uniquely associated with each subtype were overexpressed in a murine model of HPV+ HNSCC and demonstrated that HPV- associated mutations promoted the recruitment of neurons into the tumor environment. Investigations into cancer-secreted exosomes from these cell lines demonstrated the neurite outgrowth ability of these vesicles and differences in exosomal packaged miRNAs, identifying a mechanism for the differences in tumor innervation. Within the TME, these neurons have maintained functionality and facilitate cancer progression. Here, we demonstrate that substance P (SP) secretion from TRPV1+ sensory neurons bind to the endogenous NK1R receptor and promotes cell migration and proliferation. Additionally, a symbiotic relationship between cancer cells and sensory neurons was identified demonstrating the neuron-mediated function of promoting IL-6 production, resulting in the creation of an immunosuppressive immune environment through expansion and recruitment of myeloid-derived suppressor cells (MDSCs). Together, these data support the hypothesis that specific genetic mutations promote increased tumor innervation, resulting from changes in the expression and exosomal packaging of miRNAs. Additionally, once within the TME, TRPV1+ sensory neurons can contribute to cancer progression through multiple avenues of affect. Secretion of the neuropeptide SP directly binds to NK1R receptors on cancer cells, promoting cell proliferation and migration, and additionally the presence of sensory neurons produces an immunosuppressive environment through the expansion and recruitment of MDSCs. Importantly, the clinically available NK1R antagonist, Fosaprepitant, demonstrated the ability to inhibit the function of SP in our in vivo models of HNSCC, allowing for a potential rapid translation from bench to bedside.
Subject Categories
Biology
Keywords
cancer cancer neuroscience exosomes head and neck cancer Human papillomavirus miRNA
Number of Pages
162
Publisher
University of South Dakota
Recommended Citation
Restaino, Anthony, "RECRUITMENT, REPROGRAMMING, AND FUNCTION OF TRPV1+ SENSORY NERVES IN THE DEVELOPMENT AND PROGRESSION OF HEAD AND NECK CANCER" (2025). Dissertations and Theses. 359.
https://red.library.usd.edu/diss-thesis/359