Mechanical regulation of the microenvironmental niche in skin tumorigenesis

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Melanomas are histologically classified according to their location and stage of progression ranging from the congenital nevi without dysplastic changes to metastatic melanoma. The presumed precursors; benign and dysplastic nevi are characterized by the architectural disruption of the epidermal melanin unit. BRAF mutations have been implicated as a crucial step in the initiation of melanocytic neoplasia. However, melanocytic nevi can be relatively indolent for decades despite the presence of activating BRAF mutations. The role of the microenvironment is emerging as critical for malignant progression, metastasis and tumor etiology. The interactions between tumor cells and the extracellular matrix (ECM), normal cells and immune cells remain elusive. In solid tumors, dysplastic lesions remain local aberrations as long as the specialized, ECM, basement membrane (BM) remains intact. So why are some lesions quiescent while others progress rapidly to metastasis? Do tumor cells force their way through or do the structural properties of the BM simply degrade during aging? Can we determine the mechanical regulation of this motion and understand the role of the mechanical properties of the microenvironment in regulating progression to full metastatic potential?