AXL Controls Directed Migration of Mesenchymal Triple-Negative Breast Cancer Cells

Abstract

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with high risk of relapse and metastasis. TNBC is a heterogeneous disease comprising different molecular subtypes including those with mesenchymal features. The tyrosine kinase AXL is expressed in mesenchymal cells and plays a role in drug resistance, migration and metastasis. We confirm that AXL is more expressed in mesenchymal TNBC cells compared to luminal breast cancer cells, and that its invalidation impairs cell migration while having no or little effect on cell viability. Here, we found that AXL controls directed migration. We observed that AXL displays a polarized localization at the Golgi apparatus and the leading edge of migratory mesenchymal TNBC cells. AXL co-localizes with F-actin at the front of the cells. In migratory polarized cells, the specific AXL inhibitor R428 displaces AXL and F-actin from the leading edge to a lateral area localized between the front and the rear of the cells where both are enriched in protrusions. In addition, R428 treatment disrupts the polarized localization of the Golgi apparatus towards the leading edge in migratory cells. Immunohistochemical analysis of aggressive chemo-resistant TNBC samples obtained before treatment reveals inter- and intra-tumor heterogeneity of the percentage of AXL expressing tumor cells, and a preference of these cells to be in contact with the stroma. Taken together, our study demonstrates that AXL controls directed cell migration most likely by regulating cell polarity.