Cell-Autonomous versus Systemic Akt Isoform Deletions Uncovered New Roles for Akt1 and Akt2 in Breast Cancer.
Cell-Autonomous versus Systemic Akt Isoform Deletions Uncovered New Roles for Akt1 and Akt2 in Breast Cancer.
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细胞自主与系统性Akt亚型缺失揭示了Akt1和Akt2在乳腺癌中的新作用
DOI：
10.1016/j.molcel.2020.08.017
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发表时间：
2020-10-01
期刊：
影响因子：
16
通讯作者：
Hay N
中科院分区：
文献类型：
--
作者：
Chen X;Ariss MM;Ramakrishnan G;Nogueira V;Blaha C;Putzbach W;Islam ABMMK;Frolov MV;Hay N
在三种乳腺癌小鼠模型上的研究发现，在乳腺癌的发生和转移上，细胞自主性和系统性Akt1或Akt2诱导的缺失之间存在着深刻的差异。全身性Akt1缺失抑制肿瘤转移，而细胞自主性Akt1缺失则不能。单细胞信使核糖核酸测序显示，全身性Akt1缺失维持了原发瘤内的转移性聚集性，但去除了转移性中性粒细胞。系统Akt1缺失通过损害肿瘤相关中性粒细胞的存活和动员来抑制转移。重要的是，无论是全身性还是中性粒细胞特异性的Akt1缺失都足以抑制Akt熟练的肿瘤的转移。因此，Akt1的特异性抑制可能对乳腺癌的转移具有治疗作用，而不考虑原发肿瘤的来源。系统Akt2缺失并不抑制和加剧乳腺肿瘤的发生和转移，但细胞自主Akt2缺失可通过ErbB2阻止乳腺癌的发生。Akt2系统缺失引起的循环胰岛素水平升高导致肿瘤Akt过度激活，加剧ErbB2介导的肿瘤发生，并通过药物降低升高的胰岛素来抑制。Chen等人发现在肿瘤检测后可诱导的全身性Akt1缺失通过抑制肿瘤相关的中性粒细胞来抑制Akt熟练的肿瘤的乳腺癌转移。可诱导的系统Akt2缺失不能抑制乳腺癌的发生和转移。因此，特异性的Akt1抑制可以治疗乳腺癌的转移，而不考虑肿瘤的来源。
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. While 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. Chen et al. find that inducible systemic Akt1 deletion after tumor detection inhibits breast cancer metastasis of Akt-proficient tumor by inhibiting tumor-associated neutrophils. Inducible systemic Akt2 deletion does not inhibit breast cancer tumorigenesis and metastasis. Thus, specific Akt1 inhibition could be therapeutic for breast cancer metastasis regardless of tumor origin.
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影响因子：
11.2
作者：
Dillon RL;Marcotte R;Hennessy BT;Woodgett JR;Mills GB;Muller WJ
通讯作者：
Muller WJ
影响因子：
17.1
作者：
Park J;Wysocki RW;Amoozgar Z;Maiorino L;Fein MR;Jorns J;Schott AF;Kinugasa-Katayama Y;Lee Y;Won NH;Nakasone ES;Hearn SA;Küttner V;Qiu J;Almeida AS;Perurena N;Kessenbrock K;Goldberg MS;Egeblad M
通讯作者：
Egeblad M
影响因子：
64.8
作者：
Szczerba, Barbara Maria;Castro-Giner, Francesc;Aceto, Nicola
通讯作者：
Aceto, Nicola
影响因子：
--
作者：
Mellouli, Fethi;Ksouri, Habib;Bejaoui, Mohamed
通讯作者：
Bejaoui, Mohamed
影响因子：
11.2
作者：
Li CW;Xia W;Lim SO;Hsu JL;Huo L;Wu Y;Li LY;Lai CC;Chang SS;Hsu YH;Sun HL;Kim J;Yamaguchi H;Lee DF;Wang H;Wang Y;Chou CK;Hsu JM;Lai YJ;LaBaff AM;Ding Q;Ko HW;Tsai FJ;Tsai CH;Hortobagyi GN;Hung MC
通讯作者：
Hung MC