Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer.
Bieniasz-Krzywiec, P., Martin-Perez, R., Ehling, M., Garcia-Caballero, M., Pinioti, S., Pretto, S., Kroes, R., Aldeni, C., Di Matteo, M., Prenen, H., Tribulatti, M. V., Campetella, O., Smeets, A., Noel, A., Floris, G., Van Ginderachter, J. A. and Mazzone, M.
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven B3000, Belgium; Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, Brussels B1050, Belgium; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels B1050, Belgium.
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liege, Sart-Tilman, B4000 Liege, Belgium.
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven B3000, Belgium; Oncology Department, University Hospital Antwerp, 2650 Edegem, Belgium.
Institute for Research in Biotechnology, National University of San Martin, CONICET, Buenos Aires 1650, Argentina.
Surgical Oncology Unit, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven B3000, Belgium.
Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, Brussels B1050, Belgium; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels B1050, Belgium.
Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven B3000, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven B3000, Belgium. Electronic address: massimiliano.mazzone@kuleuven.vib.be.
Among mammary tumor-infiltrating immune cells, the highest expression of podoplanin (PDPN) is found in a subset of tumor-associated macrophages (TAMs). We hereby demonstrate that PDPN is involved in the attachment of this TAM subset to lymphatic endothelial cells (LECs). Mechanistically, the binding of PDPN to LEC-derived galectin 8 (GAL8) in a glycosylation-dependent manner promotes the activation of pro-migratory integrin beta1. When proximal to lymphatics, PDPN-expressing macrophages (PoEMs) stimulate local matrix remodeling and promote vessel growth and lymphoinvasion. Anti-integrin beta1 blockade, macrophage-specific Pdpn knockout, or GAL8 inhibition impairs TAM adhesion to LECs, restraining lymphangiogenesis and reducing lymphatic cancer spread. In breast cancer patients, association of PoEMs with tumor lymphatic vessels correlates with incidences of lymph node and distant organ metastasis.
Cell Metabolism : en prensa (2019)