Increased microtubule growth is required for extracellular vesicle mediated HER2 paracrine signaling to promote melanoma cancer cell invasion

The acquisition of cell invasiveness is the key transition from benign melanocyte hyperplasia to aggressive melanoma. Recent work using non-melanoma cancer cells has provided an intriguing new link between the presence of supernumerary centrosomes and increased cell invasion. Moreover, supernumerary centrosomes were shown to drive non-cell-autonomous invasion of cancer cells. Although centrosomes are the principle microtubule organizing centers the role of dynamic microtubules for non-cell-autonomous invasion remains unexplored, in particular in melanoma. We investigated the role of supernumerary centrosomes and dynamic microtubules in melanoma cell invasion and found that highly invasive melanoma cells are characterized by the presence of supernumerary centrosomes and by increased microtubule growth rates, both of which are functionally interlinked. We demonstrate that enhanced microtubule growth is required for increased 3D melanoma cell invasion. Moreover, we show that the activity to enhance microtubule growth can be transferred to adjacent non-invasive cells through extracellular vesicles harboring HER2 that are required for increased cell invasion of melanoma cells into 3D matrices. Hence, our study suggests that suppressing microtubule growth, either directly using anti-microtubule drugs or through HER2 inhibitors might be therapeutically beneficial to inhibit cell invasiveness and thus, metastasis of malignant melanoma.