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

Simple Summary Anaplastic thyroid cancer (ATC) displays a high density of tumor-associated macrophages, which modulate invasiveness and tumor growth. However, the molecular mechanisms underlying the communication between tumor cells and macrophages in ATC tumor mass are still poorly understood. Our study observed bidirectional communication mechanisms between macrophages and ATC cells, in which macrophages influenced cancer cell viability and invasive phenotype and cancer cells modulated macrophage polarization. We identified SPRY4 as a crucial mediator in this interplay, being a candidate tumor suppressor gene in this context, which may be useful to disclose new processes related to ATC aggressiveness that can lead to future therapeutic options.Abstract 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-1a; p < 0.05) in C3948-macrophage co-cultures. Proteomic analysis showed the upregulation of SPRY4, an inhibitor of the MAPK pathway, in C3948 cells from co-culture. SPRY4 silencing promoted cancer cell invasion, reverting the reduced invasion of C3948 caused by macrophages. Our findings support that macrophages play a role in ATC cell aggressiveness. SPRY4 is a possible modulator of macrophage-ATC cell communication, with a tumor suppressor role relevant for therapeutic purposes.

Automated summary

The study observed bidirectional communication mechanisms between tumor-associated macrophages and anaplastic thyroid cancer cells. The macrophages influenced cancer cell viability and invasiveness, while the cancer cells modulated macrophage polarization. The mediator SPRY4 was identified as a crucial factor in this interaction, potentially serving as a tumor suppressor gene for therapeutic purposes.