Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer due to its highly metastatic nature. Melanomas harboring oncogenic BRAFV600Emutations combined with PTEN loss exhibit unrestrained PI3K/AKT signaling and increased invasiveness. However, the contribution of different AKT isoforms to melanoma initiation, progression, and metastasis has not been comprehensively explored, and questions remain about whether individual isoforms play distinct or redundant roles in each step. We investigate the contribution of individual AKT isoforms to melanoma initiation using a novel mouse model of AKT isoform-specific loss in a murine melanoma model, and we investigate tumor progression, maintenance, and metastasis among a panel of human metastatic melanoma cell lines using AKT isoform-specific knockdown studies. We elucidate that AKT2 is dispensable for primary tumor formation but promotes migration and invasion in vitro and metastatic seeding in vivo, whereas AKT1 is uniquely important for melanoma initiation and cell proliferation. We propose a mechanism whereby the inhibition of AKT2 impairs glycolysis and reduces an EMT-related gene expression signature in PTEN-null BRAF-mutant human melanoma cells to limit metastatic spread. Our data suggest that the elucidation of AKT2-specific functions in metastasis might inform therapeutic strategies to improve treatment options for melanoma patients.
尽管近年来治疗手段有所进步，但由于其高度转移的特性，黑色素瘤仍然是皮肤癌中最致命的类型。携带致癌性BRAFV600E突变并伴有PTEN缺失的黑色素瘤表现出不受控制的PI3K/AKT信号传导和侵袭性增强。然而，不同AKT亚型对黑色素瘤发生、进展和转移的具体作用尚未得到全面探索，且各亚型在肿瘤发展的不同阶段是否发挥独特或冗余功能仍存疑问。本研究通过构建新型小鼠AKT亚型特异性缺失的黑色素瘤模型，探究了单个AKT亚型对黑色素瘤发生的影响，并利用AKT亚型特异性敲降技术，在一组人类转移性黑色素瘤细胞系中研究了肿瘤进展、维持和转移过程。我们发现AKT2对原发性肿瘤形成并非必需，但在体外能促进细胞迁移和侵袭，在体内可增强转移定植能力，而AKT1对黑色素瘤发生和细胞增殖具有独特重要性。我们提出了一种作用机制：抑制AKT2会损害糖酵解过程，并降低PTEN缺失的BRAF突变型人类黑色素瘤细胞中上皮-间质转化相关基因表达特征，从而限制转移扩散。我们的研究数据表明，阐明AKT2在转移过程中的特异性功能，可能为制定改善黑色素瘤患者治疗选择的策略提供理论依据。
肿瘤(癌症)患者之家