Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
Institute of Pathology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
J Invest Dermatol. 2023 Jul;143(7):1233-1245.e17. doi: 10.1016/j.jid.2023.01.011. Epub 2023 Jan 28.
Despite remarkable advances in treating patients with metastatic melanoma, the management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an important mechanism for the adaptation of melanoma cells to the brain environment. In this study, the methylomes and transcriptomes of a cohort of matched melanoma metastases were evaluated by integrated omics data analysis. The identified 38 candidate genes displayed distinct promoter methylation and corresponding gene expression changes in intracranial compared with extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. In accordance with the underlying promoter methylation and gene expression changes, a significantly different protein expression was confirmed for STK10, PDXK, WDR24, CSSP1, NMB, RASL11B, phosphorylated PRKCZ, PRKCZ, and phosphorylated GRB10 in the intracranial metastases. The observed changes imply a distinct intracranial phenotype with increased protein kinase B phosphorylation and a higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of phosphorylated protein kinase B and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant alterations were identified that provide insights into the molecular mechanisms that discriminate brain metastases from other organ metastases, which could be exploited by targeting the affected signaling pathways.
尽管在治疗转移性黑色素瘤患者方面取得了显著进展，但黑色素瘤脑转移的治疗仍然具有挑战性。最近的证据表明，表观遗传重编程是黑色素瘤细胞适应大脑环境的重要机制。在这项研究中，通过整合组学数据分析评估了一组匹配的黑色素瘤转移的甲基组和转录组。鉴定出的 38 个候选基因在颅内转移与颅外转移相比表现出明显的启动子甲基化和相应的基因表达变化。使用免疫组织化学在肿瘤和周围正常组织中对这 11 个最有前途的基因进行了蛋白水平验证。根据潜在的启动子甲基化和基因表达变化，在颅内转移中 STK10、PDXK、WDR24、CSSP1、NMB、RASL11B、磷酸化 PRKCZ、PRKCZ 和磷酸化 GRB10 的蛋白表达明显不同。观察到的变化表明存在明显的颅内表型，磷酸化蛋白激酶 B 的表达增加，增殖细胞的频率更高。敲低 PRKCZ 或 GRB10 改变了磷酸化蛋白激酶 B 的表达，并降低了脑特异性黑色素瘤细胞系的活力。总之，鉴定出了受表观遗传调控的与癌症相关的改变，这些改变为区分脑转移与其他器官转移的分子机制提供了深入了解，这可能通过靶向受影响的信号通路得到利用。
