Mechanical regulation of the microenvironmental niche in skin tumorigenesis

黑色素瘤根据其位置和进展阶段进行组织学分类，从没有发育不良变化的先天性痣到转移性黑色素瘤。良性和发育不良痣的特征是表皮黑色素单位的结构破坏。BRAF突变被认为是黑素细胞瘤形成的关键步骤。然而，尽管存在激活BRAF突变，黑素细胞痣可以相对惰性数十年。微环境的作用正在成为恶性进展、转移和肿瘤病因学的关键。肿瘤细胞与细胞外基质（ECM）、正常细胞和免疫细胞之间的相互作用仍然是难以捉摸的。在实体瘤中，只要特化的ECM基底膜（BM）保持完整，异型增生病变就保持局部畸变。那么，为什么有些病变是静止的，而另一些则迅速发展为转移呢？是肿瘤细胞强行通过，还是BM的结构特性在衰老过程中简单地退化？我们能否确定这种运动的机械调节，并了解微环境的机械特性在调节完全转移潜能进展中的作用？

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?