Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
Mol Cell. 2020 Oct 1;80(1):87-101.e5. doi: 10.1016/j.molcel.2020.08.017. Epub 2020 Sep 14.
Studies in three mouse models of breast cancer identified profound discrepancies between cell-autonomous and systemic Akt1- or Akt2-inducible deletion on breast cancer tumorigenesis and metastasis. Although systemic Akt1 deletion inhibits metastasis, cell-autonomous Akt1 deletion does not. Single-cell mRNA sequencing revealed that systemic Akt1 deletion maintains the pro-metastatic cluster within primary tumors but ablates pro-metastatic neutrophils. Systemic Akt1 deletion inhibits metastasis by impairing survival and mobilization of tumor-associated neutrophils. Importantly, either systemic or neutrophil-specific Akt1 deletion is sufficient to inhibit metastasis of Akt-proficient tumors. Thus, Akt1-specific inhibition could be therapeutic for breast cancer metastasis regardless of primary tumor origin. Systemic Akt2 deletion does not inhibit and exacerbates mammary tumorigenesis and metastasis, but cell-autonomous Akt2 deletion prevents breast cancer tumorigenesis by ErbB2. Elevated circulating insulin level induced by Akt2 systemic deletion hyperactivates tumor Akt, exacerbating ErbB2-mediated tumorigenesis, curbed by pharmacological reduction of the elevated insulin.
在三种乳腺癌小鼠模型的研究中，发现细胞自主和系统性 Akt1 或 Akt2 诱导缺失对乳腺癌发生和转移的影响存在显著差异。尽管系统性 Akt1 缺失抑制转移，但细胞自主 Akt1 缺失却没有。单细胞 mRNA 测序显示，系统性 Akt1 缺失在原发性肿瘤中维持了促转移簇，但消除了促转移中性粒细胞。系统性 Akt1 缺失通过抑制肿瘤相关中性粒细胞的存活和动员来抑制转移。重要的是，无论是系统性还是中性粒细胞特异性 Akt1 缺失都足以抑制 Akt 阳性肿瘤的转移。因此，无论原发性肿瘤的起源如何，针对 Akt1 的特异性抑制都可能对乳腺癌转移具有治疗作用。系统性 Akt2 缺失不能抑制和加剧乳腺肿瘤发生和转移，但细胞自主 Akt2 缺失通过 ErbB2 预防乳腺癌发生。Akt2 系统性缺失引起的循环胰岛素水平升高可使肿瘤 Akt 过度激活，加剧 ErbB2 介导的肿瘤发生，通过升高胰岛素的药物抑制可缓解这种情况。
