Intrinsic and Environmental Drivers of Thyroid Cancer

Abstract

Thyroid cancer is predicted to be the fourth most common cancer diagnosis come 2030. We were interested in understanding current drivers of the increase in cases and potential biomarkers of disease. To do so, we first investigated the role of per- and polyfluoroalkyl substances to further understand the alterations in thyroid histology and function. We also investigated the role of Tenascin-C (TNC), a secreted extracellular matrix protein, in facilitating ligand-dependent Wnt signaling in thyroid cancer. To understand the effects of PFAS on thyroid histology, we used a PFAS feeding model of a combination of three PFAS compounds (PFOS, PFOA, and GenX). This treatment of animal models showed altered thyroid architecture and cell structure following PFAS exposure. RNA-sequencing data reveled that the gene Klhl23 and multiple signaling pathways were dysregulated, including actin polymerization. Understanding the role of PFAS-mediated toxicity in the thyroid is critically important for prevention of thyroid disease in the population. Next, we utilized bulk RNA-sequencing, RNA in situ hybridization, and in vitro and in vivo models to investigate TNC. We found that TNC expression was associated with aggressive thyroid cancer behavior. Spatial localization of TNC in patient tissue demonstrated a dramatic increase in expression within cancer cells along the invasive edge, adjacent to Wnt ligand-producing fibroblasts. In vitro, TNC bound Wnt ligands and potentiated Wnt signaling. Finally, in an ATC mouse model, TNC increased Wnt signaling, tumor burden, invasion, and metastasis. Understanding the role of TNC and its interaction with Wnt ligands could lead to the development of novel biomarkers and targeted therapeutics for thyroid cancer.