Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Endocrinology & Metabolism, ENDOTHELIAL GROWTH-FACTOR, EPITHELIAL-MESENCHYMAL TRANSITION, MATRIX METALLOPROTEINASES, TUMOR LYMPHANGIOGENESIS, LYMPH-NODE, INTEGRIN, CELLS, ANGIOGENESIS, METASTASIS, BLOOD, breast cancer, lymph nodes, lymphangiogenesis, lymphoinvasion, metastasis, podoplanin, tumor-associated macrophages, Adult, Aged, Aged, 80 and over, Animals, Breast Neoplasms, Cell Line, Tumor, Endothelial Cells, Extracellular Matrix, Female, Humans, Lymph Nodes, Lymphangiogenesis, Lymphatic Metastasis, Lymphatic Vessels, Macrophages, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, META-CAN - 766214;info:eu-repo/grantAgreement/EC/H2020/766214, Immunofit - 773208;info:eu-repo/grantAgreement/EC/H2020/773208, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

Abstract:

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 β1. When proximal to lymphatics, PDPN-expressing macrophages (PoEMs) stimulate local matrix remodeling and promote vessel growth and lymphoinvasion. Anti-integrin β1 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.