Kindlin-2 regulates the growth of breast cancer tumors by activating CSF-1-mediated macrophage infiltration
Menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes par lesquels, en activant une infiltration macrophagique, la protéine Kindlin-2 favorise le processus métastatique
Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a pro-tumorigenic phenotype. In this study, we show how the integrin regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in BC biopsy tissues where its levels correlated with reduced patient survival. Based on these observations, we used CRISPR/Cas9 technology to ablate Kindlin-2 expression in human MDA-MB-231 and murine 4T1 breast cancer cells. Kindlin-2 deficiency inhibited invasive and migratory properties in vitro without affecting proliferation rates. However, in vivo tumor outgrowth was inhibited by >80% in a manner associated with reduced macrophage infiltration and secretion of the macrophage attractant and growth factor CSF-1. The observed loss of CSF-1 appeared to be caused by a more proximal deficiency in TGF-
β-dependent signaling in Kindlin-2 deficient cells. Collectively, our results illuminate a Kindlin-2/TGF-β/CSF-1 signaling axis employed by breast cancer cells to capture host macrophage functions that drive tumor progression.