SPRY4 as a Potential Mediator of the Anti-Tumoral Role of Macrophages in Anaplastic Thyroid Cancer Cells

Funding Information: This work was funded by MERCK in collaboration with Grupo de Estudos da Tiroide (GET) from Sociedade Portuguesa de Endocrinologia Diabetes e Metabolismo (SPEDM) (MERCK/GET/SPEDM/2017), by Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020) and the Associated Laboratory LS4FUTURE (LA/P/0087/2020), by Associação de Endocrinologia Oncológica (AEO/2017), and by Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG/2017). Marta Pojo was granted by Liga Portuguesa Contra o Cancro—Núcleo Regional do Sul (LPCC-NRS/2017). Carolina Pires was granted with a Ph.D. scholarship by FCT—2020.07120.BD. Ricardo Rodrigues was granted with a Ph.D. scholarship by iNOVA4Health Research Unit—UIDP/04462/2020; UI/BD/154256/2022. Publisher Copyright: © 2023 by the authors. ; Anaplastic thyroid carcinoma (ATC) is the most lethal subtype of thyroid cancer, with high invasive and metastatic potential, not responding to conventional treatments. Its aggressiveness may be influenced by macrophages, which are abundant cells in the tumor microenvironment. To investigate the role of macrophages in ATC aggressiveness, indirect co-cultures were established between ATC cell lines and THP-1-derived macrophages. Macrophages significantly increased both the migration and invasion of T235 cells (p < 0.01; p < 0.01), contrasting with a decrease in C3948 (p < 0.001; p < 0.05), with mild effects in T238 migration (p < 0.01) and C643 invasion (p < 0.05). Flow cytometry showed upregulation of CD80 (pro-inflammatory, anti-tumoral) and downregulation of CD163 (anti-inflammatory, pro-tumoral) in macrophages from co-culture with T235 (p < 0.05) and C3948 (p < 0.05), respectively. Accordingly, we found an upregulation of secreted pro-inflammatory mediators (e.g., GM-CSF, IL-1α; p < 0.05) in C3948–macrophage co-cultures. Proteomic analysis showed the upregulation of ...