CLEC18A interacts with sulfated glycosaminoglycans and controls clear cell renal cell carcinoma progression.

C-type lectins are a large protein family with essential functions in both health and disease. In cancer, some C-type lectins have been found to both promote and inhibit tumor growth, but many of the C-type lectins still remain uncharacterized. Here, we report a key role of the C-type lectin domain family 18 members (CLEC18 family) in the progression of clear cell renal cell carcinoma (ccRCC). The CLEC18 family is conserved across the entire Chordata phylum, with a high frequency of duplication events in humans compared to other species. We found that CLEC18A is exclusively expressed in the proximal tubule of the kidney and the medial habenula of the brain. We further identified sulfated glycosaminoglycans as the main CLEC18A ligand, making them unique among C-type lectins. In ccRCC patients, high expression of genes in the CLEC18 family in the tumor is associated with improved survival. In mouse models of ccRCC, deletion of the mouse ortholog, Clec18a, resulted in enhanced tumor growth. Our results establish CLEC18A as a newly identified and critical regulator of ccRCC tumor growth and highlight the potential benefit of modulating expression of CLEC18 family genes in the renal tumor microenvironment.