Syndecan-3 positively regulates the pro-inflammatory function of macrophages

Abstract

Angiogenesis; Cancer; Syndecans

Angiogénesis; Cáncer; Sindecanos

Angiogènesi; Càncer; Sindecans

The tumour microenvironment (TME) is a highly structured ecosystem that surrounds a tumour and plays a crucial role in tumorigenesis. As one of the most abundant cell types in the TME, tumour-associated-macrophages (TAMs) can promote disease progression and resistance to therapy. Syndecan-3 (SDC3) is a cell-surface heparan sulphate proteoglycan expressed by TAMs, although its functional relevance in these cells remains unknown. Here, we demonstrated that pro-inflammatory cytokines drive the expression of SDC3 on the cell surface of macrophages. Genetic ablation of SDC3 in macrophages led to aberrant proliferation, adhesion and expression of CD40 and CD86 surface markers. Moreover, SDC3 defective macrophages exhibited distinctive gene expression patterns, leading to impaired tumour cell phagocytosis and increased tumour cell proliferation. Mechanistically, a decrease in the secretion of pro-inflammatory cytokines was observed in SDC3 KO macrophages, concomitant with impaired T cell effector functions. Additionally, a higher angiogenic capacity was observed in endothelial cells when co-cultured with macrophages deficient for SDC3, possibly mediated through an increased release of VEGFA, PECAM-1 and IL-8 by SDC3 KO cells. Collectively, we have identified SDC3 as a modulator of macrophage functions aiming at supporting a pro-inflammatory and anti-tumour phenotype in these cells.

This research was supported by the European Research Council (ERC) (ERC-2018-StG 804236-NEXTGEN-IO to AP), AECC (LABAE211744PALA to AP), La Caixa Foundation (LCF/PR/HR21/52410009 to AP) and the FERO Foundation. Personal fellowships: Lorena Pérez-Gutiérrez (Juan de la Cierva: JDC2022-048612-I, AECC Talent: TALEN245896PERE), Endika Prieto-Fernández (Ramón y Cajal: RYC2021-031213-I), Asier Antoñana-Vildosola (La Caixa Inphinit: LCF/BQ/DR20/11790022), Paloma Velasco-Beltrán (PRE2020-092342 funded by MCIN/AEI /10.13039/501100011033 and by FSE:”), Alexandre Bosch (AECC: PRDVZ19003BOSC), Borja Jimenez-Lasheras (Basque Government: PRE_2019_1_0320), Ander de Blas (AECC: PRDVZ21640DEBL), Jone Etxaniz-Díaz de Durana (PRE2022-104817 funded by MCIN/AEI /10.13039/501100011033 and by FSE+), Eunate Valdaliso-Díez (PREP2022-000848 funded by MICIU/AEI/10.13039/501100011033 and by ESF+), Alena Gros (Instituto de Salud Carlos III: MS15/00058) and Asís Palazón (RYC2018-024183-I funded by MCIN/AEI /10.13039/501100011033 and by FSE; and PID2022-139344OB-I00 funded by MCIN/ AEI /10.13039/501100011033/ and by FEDER.