Brachyury and IGF1R: potential opposing roles in pediatric thyroid nodular pathology

Solid thyroid nodules are the most common presentation of thyroid cancer in children, with a higher risk of malignancy than in adults. Pediatric thyroid cancer often presents aggressively, with advanced disease, lymph node involvement, and metastasis. Papillary Thyroid Carcinoma (PTC) is the predominant type, with genetic alterations distinct from those in adults. The epithelial-to-mesenchymal transition (EMT) plays a role in tumor development and is influenced by transcription factors such as Brachyury (Brachy). Insulin-Like Growth Factors (IGFs) impact thyroid function and tumorigenesis. This study examines Brachy and Insulin-Like Growth Factor receptor type 1 (IGF1R) expression in 62 pediatric thyroid nodule samples and explores the effects of Brachy and IGF1R overexpression in Thyroid Papillary Carcinoma cells (TPC-1) both in vitro and in vivo. A total of 29 PTC, 9 follicular adenomas (FA), and 24 benign thyroid nodule (BTN) samples were analyzed. Immunohistochemical analysis revealed Brachy and IGF1R expression in papillary thyroid carcinoma and follicular adenomas but not in benign nodules. In vitro, Brachy overexpression in TPC-1 cells promoted mesenchymal traits, increasing viability, motility, and EMT markers, while IGF1R overexpression enhanced epithelial characteristics and reduced cell growth. IGF1 stimulation further increased Brachy-induced cell proliferation. In vivo, tumors derived from Brachy-overexpressing clones exhibited faster growth compared to those derived from IGF1R-overexpressing clones. Taken together, our results indicate that Brachy promotes EMT, leading to a more aggressive phenotype, while IGF1R favors epithelial features and reduces proliferation, suggesting opposing roles for Brachy and IGF1R in thyroid tumor biology.