晚期黑色素瘤是最具侵袭性的肿瘤之一,也是最致命的皮肤癌。迄今为止,组织病理学分期侧重于肿瘤厚度,临床分期是原发性黑色素瘤临床行为的主要估计。在这里,我们报告了一项观察性研究,在蛋白质水平上进行了深入的分子谱分析,包括对11例黑色素瘤患者的原发性肿瘤的翻译后修饰(PTM)。全球蛋白质组学,磷酸蛋白质组学,对每个样品进行乙酰组学。我们观察到关键线粒体功能的上调,包括线粒体翻译机制和下调参与细胞粘附的结构蛋白,细胞骨架组织,和表皮发育,这决定了疾病的进展。此外,与RNA加工和转运相关的PTM水平途径,以及染色质组织,与黑色素瘤进展有关的失调。当相似组比较或转移到原发性黑素瘤时,该队列中大多数失调的途径富含在转录水平上差异表达的基因。在基因组水平,我们发现转移性和原发性黑素瘤之间的突变谱存在显著差异.我们的发现还强调了分子谱中与性别相关的差异。值得注意的是,女性的原发性黑色素瘤显示出更高水平的抗原加工和呈递,和免疫系统反应的激活。我们的结果提供了新的见解,与为黑色素瘤患者开发个性化精准治疗相关。
Melanoma in advanced stages is one of the most aggressive tumors and the deadliest of skin cancers. To date, the histopathological staging focuses on tumor thickness, and clinical staging is a major estimate of the clinical behavior of primary melanoma. Here we report on an observational
study with in-depth molecular profiling at the protein level including post-translational modifications (PTMs) on eleven primary tumors from melanoma patients. Global proteomics, phosphoproteomics, and acetylomics were performed on each sample. We observed an up-regulation of key mitochondrial functions, including the mitochondrial translation machinery and the down-regulation of structural proteins involved in cell adhesion, the cytoskeleton organization, and epidermis development, which dictates the progression of the disease. Additionally, the PTM level pathways related to RNA processing and transport, as well as chromatin organization, were dysregulated in relation to the progression of melanoma. Most of the pathways dysregulated in this cohort were enriched in genes differentially expressed at the transcript level when similar groups are compared or metastasis to primary melanomas. At the genome level, we found significant differences in the mutation profiles between metastatic and primary melanomas. Our findings also highlighted sex-related differences in the molecular profiles. Remarkably, primary melanomas in women showed higher levels of antigen processing and presentation, and activation of the immune system response. Our results provide novel insights, relevant for developing personalized precision treatments for melanoma patients.