Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment

• Published in: Frontiers in immunology 2020-09, Vol.11, p.586977-586977
• Main Authors: Prieto-Fernández, Endika, Egia-Mendikute, Leire, Bosch, Alexandre, García Del Río, Ana, Jimenez-Lasheras, Borja, Antoñana-Vildosola, Asier, Lee, So Young, Palazon, Asis
• Format: Article
• Language: English
• Subjects: cancer immunotherapy; hypoxia; Immunology; solid tumors; syndecan-3; tumor microenvironment (TME)
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.586977

The syndecan (Sdc) family is comprised of four members of cell surface molecules (Sdc-1 to 4) with different biological functions. Syndecan-3 (Sdc-3) is known to be mainly expressed in the brain and nervous tissue and plays a key role in development, cell adhesion, and migration. Recent studies point to important roles for Sdc-3 in inflammatory disease, but the patterns of expression and significance of Sdc-3 in cancer remains unexplored. Here we show that Sdc-3 expression is upregulated on several cancer types, especially in solid tumors that are known to be hypoxic. The Cancer Genome Atlas program (TCGA) data demonstrated that Sdc-3 expression in the tumor microenvironment positively correlates with a hypoxia gene signature. To confirm a potential cause-effect, we performed experiments with tumor cell lines showing increased expression upon exposure to 1% oxygen or dimethyloxalylglycine, an inhibitor of prolyl hydroxylases, indicating that Sdc-3 expression is promoted by hypoxia inducible factors (HIFs). HIF-1α was responsible for this upregulation as confirmed by CRISPR-engineered tumor cells. Using single-cell RNA sequencing data of melanoma patients, we show that Sdc-3 is expressed on tumor associated macrophages, cancer cells, and endothelial cells. Syndecan-3 expression positively correlated with a macrophage gene signature across several TCGA cancer types. experiments demonstrated that hypoxia (1% oxygen) or treatment with IFN-γ stimulate Sdc-3 expression on RAW-264.7 derived macrophages, linking Sdc-3 expression to a proinflammatory response. Syndecan-3 expression correlates with a better patient overall survival in hypoxic melanoma tumors.