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.

Upregulated-flotillins and sphingosine kinase 2 derail vesicular trafic to stabilize AXL and promote epithelial-mesenchymal transition

“…4K). These results correlate with the recent work by Zajac et al showing the presence of AXL in LAMP1-positive vesicles in mammary tumor cells 33 . Besides, we found in flotillin-positive late endosomes other signaling transmembrane receptors and oncogenic molecules that participate in tumorigenesis, such as EphA4 and TGFβ (fig.…”

GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion

“…Accordingly, we found that AXL was accumulated in actin-rich cell regions, including lamellipodia, in glioblastoma LN229 cells. Similarly, a very recent study of Zajac et al (2020) showed that AXL colocalized with F-actin at the leading edge of migrating mesenchymal triple-negative breast cancer cells, and its depletion impaired the directionality of cell migration (Zajac et al, 2020).…”

The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

“…In Glioblastoma cells expressing high basal levels of Axl induced by GAS6, the knockdown of Axl led to reduced response to sunitinib (multi-targeted TKI) by rescuing migration [43]. In mesenchymal triple-negative breast cancer cells, Axl is localized to the Golgi apparatus and the leading edge of the migrating cell [44]. This polarization at the leading edge can be displaced by the Axl inhibitor, R438 and may indicate that Axl controls directed cell migration [44].…”