Syndecan-3 positively regulates the pro-inflammatory function of macrophages
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.
Authors
- Alena Gros (ORCID: https://orcid.org/0000-0002-1207-1880)
- Asier Antoñana-Vildosola (ORCID: https://orcid.org/0000-0002-1404-6398)
- Endika Prieto‐Fernández (ORCID: https://orcid.org/0000-0001-8378-1495)
- Arkaitz Carracedo (ORCID: https://orcid.org/0000-0001-5957-1260)
- Amaia Ercilla (ORCID: https://orcid.org/0000-0001-8999-7131)
- Asís Palazón (ORCID: https://orcid.org/0000-0002-7172-7229)
- Jose‐Ezequiel Martín (ORCID: https://orcid.org/0000-0002-0051-8868)
- Laura Bozal‐Basterra (ORCID: https://orcid.org/0000-0002-4858-2199)
- Leire Egia‐Mendikute (ORCID: https://orcid.org/0000-0002-6435-1219)
- Borja Jiménez-Lasheras (ORCID: https://orcid.org/0000-0002-1181-7492)
- Alexandre Bosch (ORCID: https://orcid.org/0000-0002-3022-7463)
- Ana M. Aransay (ORCID: https://orcid.org/0000-0002-8271-612X)
- Ander de Blas (ORCID: https://orcid.org/0000-0001-8545-2441)
- Paloma Velasco-Beltrán (ORCID: https://orcid.org/0000-0001-9686-5903)
- So Young Lee (ORCID: https://orcid.org/0000-0003-3130-785X)
- Lorena Pérez (ORCID: https://orcid.org/0000-0001-8135-4975)
- Eunate Valdaliso-Díez (ORCID: https://orcid.org/0009-0006-9447-8874)
- Jone Etxaniz-Díaz de Durana
Institutions
- Ikerbasque (ES)
- Hebron University (PS)
- Instituto de Salud Carlos III (ES)
- Vall d'Hebron Institut de Recerca (ES)
- CIC bioGUNE (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2025-04-07
- DOI
- https://doi.org/10.1007/s00018-025-05649-1
- Citations
- 4
- Primary Topic
- Proteoglycans and glycosaminoglycans research
- Type
- article
- Field-Weighted Citation Impact
- 4.61
Funders
- “la Caixa” Foundation
- Fundación Científica Asociación Española Contra el Cáncer
- Eusko Jaurlaritza
- Ministerio de Ciencia e Innovación
- Fundación Fero
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación
- European Social Fund
- FP7 Ideas: European Research Council