A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.
A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer.
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作者：
基因工程小鼠模型（GEMMs）极大地提高了我们对肿瘤进化和治疗耐药性的理解。然而，使用传统的基于cre - loxp的模型，对基因表达和宿主靶向的顺序遗传操作几乎是不可能的。我们通过结合flip - frt （flip - frt）和Cre-loxP重组技术，开发了一种可诱导的双重组酶系统，以改善胰腺癌的GEMMs。这使得研究多步骤癌变、肿瘤亚群（如癌症干细胞）的遗传操作、肿瘤微环境的选择性靶向以及全基因组范围内原位肿瘤治疗靶点的遗传验证成为可能。作为概念的证明，我们进行了肿瘤细胞自主和非自主靶向，概括了人类多步骤癌变的特征，验证了3-磷酸肌醇依赖性蛋白激酶失活和癌细胞消耗的基因治疗，并表明肿瘤微环境中的肥大细胞，被认为是关键的致癌参与者，对于肿瘤的形成是必不可少的。
Genetically engineered mouse models (GEMMs) have dramatically improved our understanding of tumor evolution and therapeutic resistance. However, sequential genetic manipulation of gene expression and targeting of the host is almost impossible using conventional Cre-loxP–based models. We have developed an inducible dual-recombinase system by combining flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies to improve GEMMs of pancreatic cancer. This enables investigation of multistep carcinogenesis, genetic manipulation of tumor subpopulations (such as cancer stem cells), selective targeting of the tumor microenvironment and genetic validation of therapeutic targets in autochthonous tumors on a genome-wide scale. As a proof of concept, we performed tumor cell–autonomous and nonautonomous targeting, recapitulated hallmarks of human multistep carcinogenesis, validated genetic therapy by 3-phosphoinositide-dependent protein kinase inactivation as well as cancer cell depletion and show that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are dispensable for tumor formation.
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影响因子：
3.8
作者：
Rajput, Ashish B.;Turbin, Dmitry A.;Cheang, Maggie C. U.;Voduc, David K.;Leung, Sam;Gelmon, Karen A.;Gilks, C. Blake;Huntsman, David G.
通讯作者：
Huntsman, David G.
影响因子：
64.8
作者：
Skarnes WC;Rosen B;West AP;Koutsourakis M;Bushell W;Iyer V;Mujica AO;Thomas M;Harrow J;Cox T;Jackson D;Severin J;Biggs P;Fu J;Nefedov M;de Jong PJ;Stewart AF;Bradley A
通讯作者：
Bradley A
肿瘤微环境中的肥大细胞促进了胰腺导管腺癌的体内生长。
DOI：
10.1158/1078-0432.ccr-11-0607
发表时间：
2011-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chang DZ;Ma Y;Ji B;Wang H;Deng D;Liu Y;Abbruzzese JL;Liu YJ;Logsdon CD;Hwu P
通讯作者：
Hwu P
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.0701117104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Carriere, Catherine;Seeley, Elliott S.;Korc, Murray
通讯作者：
Korc, Murray