AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis.
AKT2 Loss Impairs BRAF-Mutant Melanoma Metastasis.
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Akt2缺失损害BRAF-突变型黑色素瘤转移。
DOI：
10.3390/cancers15204958
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发表时间：
2023-10-12
期刊：
影响因子：
5.2
通讯作者：
Hinds, Philip W.
中科院分区：
文献类型：
--
作者：
Mcree, Siobhan K.;Bayer, Abraham L.;Pietruska, Jodie;Tsichlis, Philip N.;Hinds, Philip W.
皮肤癌，如黑色素瘤，通常是可以治疗的，但当它扩散到身体的其他部位时，就会致命，这个过程被称为转移。虽然目前许多药物都是针对黑色素瘤肿瘤生长的，但目前还没有专门预防转移的药物。因此，改善治疗效果需要了解导致转移的分子机制。AKT家族蛋白是细胞生长和信号传导的重要调节因子，在癌症中发挥着不同的作用。这项工作旨在研究AKT的每一种亚型及其在黑色素瘤细胞迁移和转移中的作用。我们发现AKT2通过影响代谢和黑色素瘤细胞特性特异性调节黑色素瘤细胞转移，而AKT1参与细胞增殖和生长。这项研究表明，特异性靶向AKT2和AKT1为不同阶段黑色素瘤患者提供了新的治疗策略。尽管最近在治疗方面取得了进展，但由于其高度转移的性质，黑色素瘤仍然是最致命的皮肤癌。携带致癌BRAFV600E突变并PTEN缺失的黑色素瘤表现出不受限制的PI3K/AKT信号传导和侵袭性增加。然而，不同的AKT亚型对黑色素瘤的发生、进展和转移的作用尚未得到全面的探讨，并且关于单个亚型是否在每个步骤中发挥独特或冗余作用的问题仍然存在。我们利用小鼠黑色素瘤模型中AKT亚型特异性缺失的新小鼠模型研究了单个AKT亚型对黑色素瘤发生的贡献，并利用AKT亚型特异性敲除研究了一组人类转移性黑色素瘤细胞系的肿瘤进展、维持和转移。我们阐明了AKT2在原发肿瘤形成中是必不可少的，但它促进体外迁移和侵袭以及体内转移播种，而AKT1在黑色素瘤的发生和细胞增殖中是唯一重要的。我们提出了一种机制，即在pten缺失的braf突变人类黑色素瘤细胞中，抑制AKT2损害糖酵解并降低emt相关基因表达特征，以限制转移性扩散。我们的数据表明，阐明转移中akt2特异性功能可能为改善黑色素瘤患者的治疗选择提供治疗策略。
Skin cancer, such as melanoma, is often treatable but becomes deadly when it expands to other places in the body, a process called metastasis. While many current drugs target melanoma tumor growth, no drugs yet exist to specifically prevent metastasis. Improving treatment outcomes, therefore, will require an understanding of the molecular mechanisms leading to metastasis. The AKT family of proteins are important regulators of cellular growth and signaling, which play differing roles in cancer. This work sought to study each of the AKT isoforms and their contributions to melanoma cell migration and metastasis. We found that AKT2 specifically regulates melanoma cell metastasis through effects on metabolism and melanoma cell properties, while AKT1 is involved in cellular proliferation and growth. This study suggests that specifically targeting AKT2 and AKT1 represents novel therapeutic strategies for different-stage melanoma patients. Despite recent advances in treatment, melanoma remains the deadliest form of skin cancer due to its highly metastatic nature. Melanomas harboring oncogenic BRAFV600E mutations 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.
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DOI：
10.1093/noajnl/vdaa140
发表时间：
2020-01
期刊：
Neuro-oncology advances
影响因子：
--
作者：
Amaral T;Niessner H;Sinnberg T;Thomas I;Meiwes A;Garbe C;Garzarolli M;Rauschenberg R;Eigentler T;Meier F
通讯作者：
Meier F
影响因子：
5.2
作者：
Bayer AL;Pietruska J;Farrell J;McRee S;Alcaide P;Hinds PW
通讯作者：
Hinds PW
影响因子：
50.3
作者：
Chae YC;Vaira V;Caino MC;Tang HY;Seo JH;Kossenkov AV;Ottobrini L;Martelli C;Lucignani G;Bertolini I;Locatelli M;Bryant KG;Ghosh JC;Lisanti S;Ku B;Bosari S;Languino LR;Speicher DW;Altieri DC
通讯作者：
Altieri DC
影响因子：
8
作者：
Goel, V. K.;Ibrahim, N.;Jiang, G.;Singhal, M.;Fee, S.;Flotte, T.;Westmoreland, S.;Haluska, F. S.;Hinds, P. W.;Haluska, F. G.
通讯作者：
Haluska, F. G.
影响因子：
11.2
作者：
Alonso, Soledad R.;Tracey, Lorraine;Rodriguez-Peralto, Jose L.
通讯作者：
Rodriguez-Peralto, Jose L.