Promotion of tumor invasion and pseudosenescence by the aging microenvironment

描述（由申请人提供）：恶性黑色素瘤是一种侵袭性疾病，治疗选择有限。特别是，55岁以上的个体与年轻人相比，相同级别和分期的黑色素瘤的预后要差得多。到目前为止，还没有人解释黑色素瘤在衰老个体中侵袭性和转移性差异的原因。我们的长期目标是验证衰老微环境驱动黑色素瘤细胞局部侵袭性和系统性传播的假设。在之前的工作中，我们通过分泌因子Wnt5a确定了调节黑色素瘤侵袭的关键信号通路。我们发现具有高Wnt5A的黑色素瘤具有间质表型，迁移和侵袭倾向增加，并且预后较差显著相关。在这项应用的初步数据中，我们发现黑色素瘤与来自老年人的成纤维细胞共同培养，而不是来自年轻人的成纤维细胞，诱导它们表达高Wnt5a水平、间充质表型和增加的侵袭性。有趣的是，我们还发现黑色素瘤与衰老而非年轻的成纤维细胞共培养显示出衰老样表型的证据。我们的初步数据暗示黑色素瘤与来自老年人的成纤维细胞共同培养。我们发现衰老的成纤维细胞持续降低Klotho的表达，Klotho是Wnt5A信号传导和衰老的有效抑制剂。我们假设，老年肿瘤微环境中Klotho表达的降低有助于Wnt5A信号的增加和老年黑色素瘤的侵袭性增加。拟议的研究将使人们更好地了解Klotho和衰老微环境在55岁以上患者黑色素瘤中增加的侵袭性和侵袭性中的作用。我们希望阐明Klotho和Wnt5a在黑色素瘤衰老过程中的作用，从而改善治疗方法。

DESCRIPTION (provided by applicant): Malignant melanoma is an aggressive disease for which there are limited therapeutic options. In particular, individuals over the age of 55 have a much poorer prognosis for melanomas of equal grade and stage, compared to younger individuals. To date, no one has addressed the reasons for this disparity in melanoma aggressiveness and metastasis in aging individuals. Our long-term objective is test the hypothesis that the aging microenvironment drives the local aggressiveness and systemic dissemination of melanoma cells. In previous work we identified a critical signaling pathway that modulates melanoma invasiveness, by the secreted factor Wnt5a. We have found that melanomas with high Wnt5A have a mesenchymal phenotype, an increased propensity to migrate and invade, and are significantly associated with poorer prognosis. In preliminary data for this application we show that co-culture of melanomas with fibroblasts from aged individuals, but not young individuals, induces them to express high Wnt5a levels, a mesenchymal phenotype, and increased invasiveness. Interestingly, we have also discovered that melanomas co-cultured with aged but not young fibroblasts show evidence for a senescent-like phenotype. Our preliminary data implicate the co-culture of melanomas with fibroblasts from aged individuals. We find that aged fibroblasts consistently decrease their expression of Klotho, and that Klotho is a potent inhibitor of Wnt5A signaling and senescence. We hypothesize that the decreased expression of Klotho within the aged tumor micro-environment contributes to increased Wnt5A signaling and increased invasiveness in melanomas in the elderly. The proposed studies will lead to an improved understanding of the role of Klotho and the aging micro-environment in the increased aggressiveness and invasiveness seen in melanomas in patients over the age of 55. It is expected that elucidating the role of Klotho and Wnt5a in melanomas in aging will lead to improved therapy.