Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis.
Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis.
复制标题
DOI：
10.1038/nm.4285
复制
发表时间：
2017-03
期刊：
影响因子：
82.9
通讯作者：
Winslow MM
中科院分区：
文献类型：
--
作者：
Chuang CH;Greenside PG;Rogers ZN;Brady JJ;Yang D;Ma RK;Caswell DR;Chiou SH;Winters AF;Grüner BM;Ramaswami G;Spencley AL;Kopecky KE;Sayles LC;Sweet-Cordero EA;Li JB;Kundaje A;Winslow MM
肺癌是全球癌症死亡的主要原因，其中大部分死亡率由转移性扩散引起。然而，癌细胞获得从原发性肿瘤扩散、在远处器官播种并生长成组织破坏性转移灶的能力的分子机制仍不完全清楚。我们将人肺腺癌小鼠模型中的肿瘤条形码与无偏基因组方法相结合，以确定赋予转移能力并预测患者生存的转录程序。小规模的体内筛选确定了几个基因，包括Cd 109，编码新的促转移因子。我们发现由Janus激酶（Jaks）和转录因子Stat 3介导的信号传导是CD 109驱动的肺癌转移的关键、可靶向的效应子。总之，通过将来自小鼠模型的不同恶性状态的纯化癌细胞的系统基因组分析与广泛的人类验证相结合，我们发现了转移能力的几个关键调节因子，包括可操作的促转移CD 109-Jak-Stat 3轴。
Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109–Jak–Stat3 axis.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
4.8
作者：
Greenleaf, William J.
通讯作者：
Greenleaf, William J.
影响因子：
64.8
作者：
Clark, EA;Golub, TR;Hynes, RO
通讯作者：
Hynes, RO
使用逆行病毒载体递送和体内 CRISPR/Cas9 介导的体细胞基因组编辑进行胰腺癌建模。
影响因子：
10.5
作者：
Chiou SH;Winters IP;Wang J;Naranjo S;Dudgeon C;Tamburini FB;Brady JJ;Yang D;Grüner BM;Chuang CH;Caswell DR;Zeng H;Chu P;Kim GE;Carpizo DR;Kim SK;Winslow MM
通讯作者：
Winslow MM
影响因子：
50.3
作者：
Brady JJ;Chuang CH;Greenside PG;Rogers ZN;Murray CW;Caswell DR;Hartmann U;Connolly AJ;Sweet-Cordero EA;Kundaje A;Winslow MM
通讯作者：
Winslow MM