Oncogenic Kras drives invasion and maintains metastases in colorectal cancer

被引：161

作者：

Boutin, Adam T. ^{[1
]}

Liao, Wen-Ting ^{[1
]}

Wang, Melody ^{[1
]}

Hwang, Soyoon Sarah ^{[1
]}

Karpinets, Tatiana V. ^{[2
]}

Cheung, Hannah ^{[2
]}

Chu, Gerald C. ^{[3
]}

Jiang, Shan ^{[2
]}

Hu, Jian ^{[1
]}

Chang, Kyle ^{[4
]}

Vilar, Eduardo ^{[4
,5
]}

Song, Xingzhi ^{[3
]}

Zhang, Jianhua ^{[3
]}

Kopetz, Scott ^{[5
]}

Futreal, Andrew ^{[2
]}

Wang, Y. Alan ^{[1
]}

Kwong, Lawrence N. ^{[2
,6
]}

DePinho, Ronald A. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

来源：

GENES & DEVELOPMENT | 2017年 / 31卷 / 04期

基金：

美国国家卫生研究院;

关键词：

colorectal cancer; metastasis; Kras; Apc; P53; invasion; MULTIPLE INTESTINAL NEOPLASIA; CRE-MEDIATED RECOMBINATION; MOUSE MODEL; ACQUIRED-RESISTANCE; TGF-BETA; APC; RAS; MUTATION; ADENOMA; TUMORS;

D O I：

10.1101/gad.293449.116

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Human colorectal cancer (CRC) is a major cause of cancer mortality and frequently harbors activating mutations in the KRAS gene. To understand the role of oncogenic KRAS in CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenic Kras allele (Kras(mut)) and conditional null alleles of Apc and Trp53 (iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that the Kras(mut) allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Kras(mut) signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-beta pathway as a key mediator of Kras(mut)-driven invasiveness. Genetic extinction of Kras(mut) resulted in specific elimination of the Kras(mut) subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Kras(mut) drives CRC invasion and maintenance of metastases.

引用

页码：370 / 382

页数：13

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