Cross-talk between the receptor tyrosine kinases AXL and ERBB3 regulates invadopodia formation in melanoma cells

Abstract

The invasive phenotype of metastatic cancer cells is accompanied by the formation of actin-rich invadopodia, which adhere to the extracellular matrix, and degrade it.In this study, we explored the role of the tyrosine kinome in the formation of invadopodia in metastatic melanoma cells. Using a microscopy-based siRNA screen, we identified novel invadopodia regulators, the knock-down of which either suppresses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances invadopodia formation and function (e.g., ABL2, AXL, CSK). Particularly intriguing was the discovery that the receptor tyrosine kinase AXL displays a dual regulatory function, manifested by enhancement of invadopodia function upon knock-down or long-term inhibition, as well as following its over-expression. We show here that this apparent contradiction may be attributed to the capacity of AXL to directly stimulate invadopodia; yet its suppression up-regulates the ERBB3 signaling pathway, which consequently activates core invadopodia regulators, and greatly enhances invadopodia function.Bioinformatic analysis of multiple melanoma cells points to an inverse expression pattern of AXL and ERBB3, with the apparent association of high-AXL melanomas, with high expression of invadopodia components and an invasive phenotype. The relevance of these results to melanoma metastasis in vivo, and to potential anti-invasion therapy, is discussed.

ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

“…The AXL receptor kinase is known to play a critical role in cell proliferation, survival, cancer stem cell maintenance, and metastasis in several cancers 25 , and has been associated with melanoma cell motility, invasion, and drug resistance [30][31][32] . Thus, it represents a reasonable candidate for mediating the proinvasive effects of ST3GAL1.…”

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

“…An increased expression of AXL in highly metastatic breast cancer was found to be essential for all steps of the metastatic process, starting with intravasation of cancer cells (Goyette et al, 2018). Consistently with the association of AXL with cancer invasion and metastasis, a very recent study of Revach et al (2019) reported that AXL may regulate the formation of invadopodia in melanoma cells. Furthermore, AXL has been linked to epithelial-tomesenchymal transition (EMT) that is associated with metastasis (Chaffer et al, 2016;Diepenbruck & Christofori, 2016).…”

“…Since mesenchymal migration of cancer cells requires constant disassembly of existing FAs and assembly of new ones, our results indicate that the GAS6-AXL signaling pathway may regulate these processes, partially by triggering the formation of CDRs. AXL was recently shown to stimulate the formation and activity of invadopodia in melanoma cells (Revach et al, 2019). This is another type of actin-based protrusions important for cancer metastasis, as they degrade and remodel the ECM (Eddy et al, 2017).…”

Orbital involvement by NUT midline carcinoma: new presentation and encouraging outcome managed by radiotherapy combined with tyrosine kinase inhibitor: a case report

“…Receptor tyrosine kinases (RTKs) are transmembrane glycoproteins that communicate with cellular growth factors and extracellular ligands [11]. They play vital roles in intracellular tyrosine phosphorylation and intracellular signaling [12].…”