Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer

• Published in: Cell metabolism Vol. 30; no. 5; pp. 917 - 936.e10
• Main Authors: Bieniasz-Krzywiec, Paweł, Martín-Pérez, Rosa, Ehling, Manuel, García-Caballero, Melissa, Pinioti, Sotiria, Pretto, Samantha, Kroes, Roel, Aldeni, Chiara, Di Matteo, Mario, Prenen, Hans, Tribulatti, María Virginia, Campetella, Oscar, Smeets, Ann, Noel, Agnes, Floris, Giuseppe, Van Ginderachter, Jo A, Mazzone, Massimiliano
• Format: Journal Article Web Resource
• Language: English
• Published: United States Cell Press 05.11.2019
• Subjects: Adult; Aged; Aged, 80 and over; Animals; breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Endothelial Cells - metabolism; Extracellular Matrix - metabolism; Female; Human health sciences; Humans; lymph nodes; Lymph Nodes - pathology; lymphangiogenesis; Lymphangiogenesis - genetics; Lymphatic Metastasis - genetics; Lymphatic Vessels - metabolism; lymphoinvasion; Macrophages - metabolism; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Oncologie; Oncology; podoplanin; Sciences de la santé humaine; tumor-associated macrophages; lymph nodes; metastasis; lymphangiogenesis; lymphoinvasion; breast cancer; podoplanin; tumor-associated macrophages
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2019.07.015

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.