Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth.
Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth.
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DOI：
10.1038/s41556-018-0218-9
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发表时间：
2018-11
影响因子：
21.3
通讯作者：
Beronja S
中科院分区：
文献类型：
--
作者：
Ying Z;Sandoval M;Beronja S
令人惊讶的是，致癌病变在形态和功能正常的人类皮肤中非常常见，然而，抑制其致癌潜力以维持组织稳态的细胞和分子机制尚不清楚。通过采用体内细胞命运选择的直接和定量评估分析，我们发现 PI3K/AKT 的致癌激活（癌症中最常见的激活致癌途径）可促进表皮祖细胞的分化和细胞周期退出。因此，致癌 PI3K/AKT 激活的表皮表现出生长劣势，尽管其细胞更具增殖性。为了揭示癌基因诱导分化背后的潜在机制，我们进行了一系列体内遗传筛选，并鉴定出 AKT 底物 SH3RF1 作为表皮分化的特异性启动子，且对增殖没有影响。我们的研究为直接的细胞自主机制提供了证据，该机制可以抑制祖细胞更新并阻止带有 Pik3ca 常见激活突变的表皮细胞的克隆扩张。
Oncogenic lesions are surprisingly common in morphologically and functionally normal human skin, however, the cellular and molecular mechanisms that suppress their cancer-driving potential to maintain tissue homeostasis are unknown. By employing assays for direct and quantitative assessment of cell fate choices in vivo, we show that oncogenic activation of PI3K/AKT, the most commonly activated oncogenic pathway in cancer, promotes differentiation and cell-cycle exit of epidermal progenitors. As a result, oncogenic PI3K/AKT activated epidermis exhibits growth disadvantage even though its cells are more proliferative. To uncover the underlying mechanism behind oncogene-induced differentiation, we conduct a series of genetic screens in vivo, and identify an AKT substrate SH3RF1 as a specific promoter of epidermal differentiation that has no effect on proliferation. Our study provides evidence for a direct, cell autonomous mechanism that can suppresses progenitor cell renewal and block clonal expansion of epidermal cells bearing a common and activating mutation in Pik3ca.
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影响因子：
8
作者：
Du L;Chen X;Cao Y;Lu L;Zhang F;Bornstein S;Li Y;Owens P;Malkoski S;Said S;Jin F;Kulesz-Martin M;Gross N;Wang XJ;Lu SL
通讯作者：
Lu SL
食管鳞状细胞癌的空间瘤内异质性和时间克隆进化
影响因子：
30.8
作者：
Hao, Jia-Jie;Lin, De-Chen;Dinh, Huy Q.;Mayakonda, Anand;Jiang, Yan-Yi;Chang, Chen;Jiang, Ye;Lu, Chen-Chen;Shi, Zhi-Zhou;Xu, Xin;Zhang, Yu;Cai, Yan;Wang, Jin-Wu;Zhan, Qi-Min;Wei, Wen-Qiang;Berrnan, Benjamin P.;Wang, Ming-Rong;Koeffler, H. Phillip
通讯作者：
Koeffler, H. Phillip
DOI：
10.1158/1078-0432.ccr-14-1773
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li YY;Hanna GJ;Laga AC;Haddad RI;Lorch JH;Hammerman PS
通讯作者：
Hammerman PS
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
14.9
作者：
Hornbeck PV;Kornhauser JM;Tkachev S;Zhang B;Skrzypek E;Murray B;Latham V;Sullivan M
通讯作者：
Sullivan M