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SOX2/SOX17 Molecular Switching by Polyphenols to Promote Thyroid Differentiation in 2D and 3D Models of Anaplastic Thyroid Cancer †
by
, , , and
Fabiola Vaglica
1,‡, 
Mattia Biondo
2,‡,
Giuseppe Siragusa
2,
Giorgio Arnaldi
1,
Valentina Guarnotta
1,*,
Giuseppe Pizzolanti
1,3,§ and
Laura Tomasello
1,§ 1
Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro” (Promise), University of Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy
2
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (Stebicef), University of Palermo, Viale delle Scienze, Ed. 16, 90128 Palermo, PA, Italy
3
Advanced Technologies Network (ATeN) Center, Viale delle Scienze-Edificio 18/A, 90128 Palermo, PA, Italy
*
Author to whom correspondence should be addressed.
†
This paper is extended version of paper published in Vaglica, F.; Tomasello, L.; Biondo, M.; Siragusa, G.; Arnaldi, G.; Pizzolanti, G. Polyphenols As A Potential Strategy In Overcoming Therapy Resistance In Anaplastic Thyroid Cancer Through The Sox2-Sox17 Molecular Switch, 97 Ed., Congress of the Società Italiana di Biologia Sperimentale (SIBS), Palermo, Italy, 10–13 April 2025; Tomasello, L.; Vaglica, F.; Biondo, M.; Siragusa, G.; Arnaldi, G.; Guarnotta, V.; Pizzolanti, G. Strategie per Limitare La Resistenza Alle Terapie Del Carcinoma Anaplastico Tiroideo: Uso Di Polifenoli Per Influenzare Il Differenziamento Delle Cellule Tumorali, 43 Ed., Congress of the Società Italiana di Endocrinologia (SIE), Torino, Italy, 11–14 June 2025.
‡
These authors contributed equally to this work.
§
These authors shared the last position.
Biology 2025, 14(12), 1730; https://doi.org/10.3390/biology14121730 (registering DOI)
Submission received: 20 October 2025
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Revised: 21 November 2025
/
Accepted: 1 December 2025
/
Published: 2 December 2025
(This article belongs to the Special Issue Experimental Biology 100 Years After the Foundation of the Italian Society: A Celebratory Special Issue)
Simple Summary
One of the most aggressive types of thyroid cancer, anaplastic thyroid cancer, frequently resists standard therapies like chemotherapy, radiotherapy, and surgery. This resistance mainly results from the loss of the normal gene expression profile of thyroid cells, which acquire features like cancer stem cells (CSCs). This behavior has been linked to an altered balance between two key regulatory genes, SOX2 and SOX17, which determine whether a cell remains undifferentiated or becomes specialized. In this study, we investigated whether natural plant-derived compounds known as polyphenols (resveratrol and two of its natural analogs) could help thyroid cancer cells regain normal functional characteristics and become more responsive to conventional therapies. Using a three-dimensional culture model that more accurately reproduces the architecture and growth conditions of human tumors, we found that these compounds slow cell proliferation and promote a transition from a stem-like to a more differentiated cell type by rebalancing SOX2 and SOX17 expression levels. These findings suggest that polyphenols may act as supportive agents for standard treatments and could open new perspectives for the management of highly aggressive thyroid cancers.
Abstract
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.
