Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer

BIENIASZ-KRZYWIEC, PAWE?; 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

CELL METABOLISM

CELL PRESS

Lugar: United States; Año: 2019 vol. 30 p. 917 - 936

1550-4131

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 pro- motes the activation of pro-migratory integrin b1. When proximal to lymphatics, PDPN-expressing macrophages (PoEMs) stimulate local matrix remod- eling and promote vessel growth and lymphoinva- sion. Anti-integrin b1 blockade, macrophage-spe- cific Pdpn knockout, or GAL8 inhibition impairs TAM adhesion to LECs, restraining lymphangiogene- sis and reducing lymphatic cancer spread. In breastcancer patients, association of PoEMs with tumor lymphatic vessels correlates with incidences of lymph node and distant organ metastasis.