SOX2/SOX17 Molecular Switching by Polyphenols to Promote Thyroid Differentiation in 2D and 3D Models of Anaplastic Thyroid Cancer

Deep alterations in tumor cell gene profiles resulting in the loss of their specific functions are frequently the cause of resistance to traditional cancer treatments. Therefore, reprogramming the expression pattern of cancer cells toward a differentiated phenotype represents a promising therapeutic strategy. In this study, we investigated whether resveratrol (RSV) and its natural analogs—3,4′,5-trimethoxystilbene (3-MET-OX) and isorhapontigenin (ISOR-H-PG)—can modulate the SOX2/SOX17 balance and promote re-differentiation in anaplastic thyroid cancer (ATC) cells. Two human ATC cell lines (SW1736 and 8505c) and non-tumoral thyroid cells (Nthy-ori 3-1) were cultured in two-dimensional (2D) or three-dimensional (3D) systems and treated with polyphenols at sub-cytotoxic doses. In 2D cultures, cell viability and cell cycle analyses confirmed a cytostatic effect characterized by G1 arrest. In 3D cultures, polyphenol treatment caused morphological disruption of ATC spheroids and significantly modulated the gene expression profile. RSV and 3-MET-OX reduced stemness markers (SOX2, NANOG), increased the thyroid lineage transcription factor (SOX17), and enhanced differentiation genes (TTF-1, TPO, NIS). Overall, these results support our hypothesis that modulation of the SOX2/SOX17 ratio by polyphenols provides a mechanistic basis for re-differentiation, thereby improving therapeutic responsiveness in ATC.