Increased Microtubule Growth Triggered by Microvesicle-mediated Paracrine Signaling is Required for Melanoma Cancer Cell Invasion

Abstract

The acquisition of cell invasiveness is the key transition from benign melanocyte hyperplasia to aggressive melanoma. Recent work 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 principal 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 three-dimensional melanoma cell invasion. Moreover, we show that the activity to enhance microtubule growth can be transferred onto adjacent noninvasive cells through microvesicles involving HER2. 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. Significance: This study shows that increased microtubule growth is required for melanoma cell invasion and can be transferred onto adjacent cells in a non–cell-autonomous manner through microvesicles involving HER2.