Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer.
Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer.
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DOI：
10.1016/j.ccell.2020.08.015
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发表时间：
2020-10-12
期刊：
影响因子：
50.3
通讯作者：
Astsaturov I
中科院分区：
文献类型：
--
作者：
Gabitova-Cornell L;Surumbayeva A;Peri S;Franco-Barraza J;Restifo D;Weitz N;Ogier C;Goldman AR;Hartman TR;Francescone R;Tan Y;Nicolas E;Shah N;Handorf EA;Cai KQ;O'Reilly AM;Sloma I;Chiaverelli R;Moffitt RA;Khazak V;Fang CY;Golemis EA;Cukierman E;Astsaturov I
致癌转化改变脂质代谢以维持肿瘤生长。我们确定了胆固醇代谢控制胰腺导管腺癌（PDAC）发展和分化的机制。在KrasG 12 D表达和纯合Trp 53缺失驱动的小鼠模型中，通过限速酶Nsdhl的条件性失活或用降胆固醇他汀类药物治疗来破坏远端胆固醇生物合成将胰腺腺癌转变为基底（间充质）表型。一致地，接受他汀类药物治疗的患者的PDAC显示增强的间充质特征。从机制上讲，他汀类药物和NSDHL损失诱导SREBP 1激活，这促进了Tgfb 1的表达，从而实现上皮-间充质转化。本研究中来自患者样本的证据表明，降胆固醇他汀类药物激活TGFβ信号传导和上皮-间质转化可能促进基础型PDAC，从而导致患者结局不良。Gabitova-Cornell等人表明，通过Nsdh 1敲除或他汀类药物治疗破坏胆固醇生物合成，通过激活SREBP 1将胰腺腺癌转变为基底亚型，SREBP 1诱导Tgfb 1表达和自分泌TGFβ-SMAD 2/3信号传导，诱导上皮-间充质转化。
Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by KrasG12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1 enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests activation of TGFβ signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote basal type of PDAC conferring poor outcomes in patients. Gabitova-Cornell et al. show that disruption of cholesterol biosynthesis by Nsdhl knockout or treatment with statins switches glandular pancreatic carcinomas to a basal subtype via activation of SREBP1, which induces Tgfb1 expression and autocrine TGFβ-SMAD2/3 signaling, inducing epithelial-mesenchymal transition.
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影响因子：
28.2
作者：
Dominguez, Claudia X.;Mueller, Soren;Turley, Shannon J.
通讯作者：
Turley, Shannon J.
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
6.5
作者：
Cunningham, D;Swartzlander, D;Herman, GE
通讯作者：
Herman, GE
影响因子：
64.5
作者：
David CJ;Huang YH;Chen M;Su J;Zou Y;Bardeesy N;Iacobuzio-Donahue CA;Massagué J
通讯作者：
Massagué J
DOI：
10.1158/1078-0432.ccr-17-2994
发表时间：
2018-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Aung KL;Fischer SE;Denroche RE;Jang GH;Dodd A;Creighton S;Southwood B;Liang SB;Chadwick D;Zhang A;O'Kane GM;Albaba H;Moura S;Grant RC;Miller JK;Mbabaali F;Pasternack D;Lungu IM;Bartlett JMS;Ghai S;Lemire M;Holter S;Connor AA;Moffitt RA;Yeh JJ;Timms L;Krzyzanowski PM;Dhani N;Hedley D;Notta F;Wilson JM;Moore MJ;Gallinger S;Knox JJ
通讯作者：
Knox JJ