ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma

SIMPLE SUMMARY: Metastasis formation and dissemination is a complex process that relies on several steps. Even though highly inefficient, metastasis spreading is the primary cause of cancer morbidity and mortality in patients. The aim of our study was to investigate the molecular pathways leading to metastases making use of human-in-mouse melanoma models of patient-derived xenografts. We demonstrate that the modulation of the expression of an adaptor protein of the Shc family, ShcD, can change the phenotype and the invasive properties of melanoma cells when highly expressed. We also show that ShcD binds DOCK4 and confines it into the cytoplasm, blocking the Rac1 signaling pathways, thus leading to metastasis development. Moreover, our results indicate that melanoma cells are more sensitive to therapeutic treatments when the ShcD molecular pathway is inactivated, suggesting that new therapeutic strategies can be designed in melanomas. ABSTRACT: Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation of metastatic-specific signaling pathways in the primary melanoma. In the current study, we investigated the role of an adaptor protein of the Shc family (ShcD) in the acquisition of metastatic properties by melanoma cells, exploiting our cohort of patient-derived xenografts (PDXs). We provide evidence that the depletion of ShcD expression increases a spread cell shape and the capability of melanoma cells to attach to the extracellular matrix while its overexpression switches their morphology from elongated to rounded on 3D matrices, enhances cells’ invasive phenotype, as observed on collagen gel, and favors metastasis formation in vivo. ShcD overexpression sustains amoeboid movement in melanoma cells, by suppressing the Rac1 signaling pathway through the confinement of DOCK4 in the cytoplasm. Inactivation of the ShcD signaling pathway makes melanoma cells more sensitive to therapeutic treatments. Consistently, ShcD expression predicts poor outcome in a cohort of 183 primary melanoma patients.