American Association for Cancer Research
00085472can182316-sup-205963_2_supp_5353685_pwm2k8.docx (12.14 MB)

Figure S1-S5, Table S1 from Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells

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journal contribution
posted on 2023-03-31, 01:43 authored by Or-Yam Revach, Oded Sandler, Yardena Samuels, Benjamin Geiger

In the file an additional information on the screen workflow and characterization of the effects of the genes that were found in the screen on invadopodia formation. Further there is Supplementary Table 1 (screen results for 63T cells). In addition, there are supplementary experiments supporting the role of AXL as a regulator of invadopodia in melanoma, as well as breast cancer cells.


Israel Ministry of Science

Israel Science Foundation




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 a series of regulators, the knockdown of which either suppresses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances (e.g., ABL2, AXL, CSK) invadopodia formation and function. Notably, the receptor tyrosine kinase AXL displayed a dual regulatory function, where both depletion or overexpression enhanced invadopodia formation and activity. This apparent contradiction was attributed to the capacity of AXL to directly stimulate invadopodia, yet its suppression upregulates the ERBB3 signaling pathway, which can also activate core invadopodia regulators and enhance invadopodia function. Bioinformatic analysis of multiple melanoma cell lines points to an inverse expression pattern of AXL and ERBB3. High expression of AXL in melanoma cells is associated with high expression of invadopodia components and an invasive phenotype. These results provide new insights into the complexity of metastasis-promoting mechanisms and suggest that targeting of multiple invadopodia signaling networks may serve as a potential anti-invasion therapy in melanoma. These findings uncover a unique interplay between AXL and ERBB3 in invadopodia regulation that points to the need for combined therapy in order to prevent invadopodia-mediated metastasis in melanoma.