<i>FOXE1</i>-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo

• Main Authors: Sara C. Credendino, Marta De Menna, Irene Cantone, Carmen Moccia, Matteo Esposito, Luigi Di Guida, Mario De Felice, Gabriella De Vita
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: International Journal of Molecular Sciences
• Subjects: FOXE1; chemokines; TAMs; tumour microenvironment
• Online Access: https://www.mdpi.com/1422-0067/22/14/7666

Forkhead box E1 (<i>FOXE1</i>) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse <i>FOXE1</i>-induced transcriptional alterations in thyroid cells that do not express endogenous <i>FOXE1</i>. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, <i>FOXE1</i>-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if <i>FOXE1</i> was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional <i>FOXE1</i> allele. Expression of the same set of chemokines directly correlates with <i>FOXE1</i> dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced <i>FOXE1</i>. These data establish a novel link between <i>FOXE1</i> and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression.