Oncogenic Kras drives invasion and maintains metastases in colorectal cancer

Adam T. Boutin; Wen Ting Liao; Melody Wang; Soyoon Sarah Hwang; Tatiana V. Karpinets; Hannah Cheung; Gerald C. Chu; Shan Jiang; Jian Hu; Kyle Chang; Eduardo Vilar; Xingzhi Song; Jianhua Zhang; Scott Kopetz; Andrew Futreal; Y. Alan Wang; Lawrence N. Kwong; Ronald A. DePinho

doi:10.1101/gad.293449.116

Oncogenic Kras drives invasion and maintains metastases in colorectal cancer

Adam T. Boutin, Wen Ting Liao, Melody Wang, Soyoon Sarah Hwang, Tatiana V. Karpinets, Hannah Cheung, Gerald C. Chu, Shan Jiang, Jian Hu, Kyle Chang, Eduardo Vilar, Xingzhi Song, Jianhua Zhang, Scott Kopetz, Andrew Futreal, Y. Alan Wang, Lawrence N. Kwong, Ronald A. DePinho

Research output: Contribution to journal › Article › peer-review

126 Scopus citations

Abstract

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-β 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.

Original language	English (US)
Pages (from-to)	370-382
Number of pages	13
Journal	Genes and Development
Volume	31
Issue number	4
DOIs	https://doi.org/10.1101/gad.293449.116
State	Published - Feb 15 2017

Keywords

Apc
Colorectal cancer
Invasion
Kras
Metastasis
P53

ASJC Scopus subject areas

Genetics
Developmental Biology

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10.1101/gad.293449.116

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Boutin, A. T., Liao, W. T., Wang, M., Hwang, S. S., Karpinets, T. V., Cheung, H., Chu, G. C., Jiang, S., Hu, J., Chang, K., Vilar, E., Song, X., Zhang, J., Kopetz, S., Futreal, A., Wang, Y. A., Kwong, L. N., & DePinho, R. A. (2017). Oncogenic Kras drives invasion and maintains metastases in colorectal cancer. Genes and Development, 31(4), 370-382. https://doi.org/10.1101/gad.293449.116

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title = "Oncogenic Kras drives invasion and maintains metastases in colorectal cancer",

abstract = "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 (Krasmut) 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 Krasmut allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Krasmut signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of Krasmut-driven invasiveness. Genetic extinction of Krasmut resulted in specific elimination of the Krasmut subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Krasmut drives CRC invasion and maintenance of metastases.",

keywords = "Apc, Colorectal cancer, Invasion, Kras, Metastasis, P53",

author = "Boutin, {Adam T.} and Liao, {Wen Ting} and Melody Wang and Hwang, {Soyoon Sarah} and Karpinets, {Tatiana V.} and Hannah Cheung and Chu, {Gerald C.} and Shan Jiang and Jian Hu and Kyle Chang and Eduardo Vilar and Xingzhi Song and Jianhua Zhang and Scott Kopetz and Andrew Futreal and Wang, {Y. Alan} and Kwong, {Lawrence N.} and DePinho, {Ronald A.}",

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doi = "10.1101/gad.293449.116",

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AU - Boutin, Adam T.

AU - Liao, Wen Ting

AU - Wang, Melody

AU - Hwang, Soyoon Sarah

AU - Karpinets, Tatiana V.

AU - Cheung, Hannah

AU - Chu, Gerald C.

AU - Jiang, Shan

AU - Hu, Jian

AU - Chang, Kyle

AU - Vilar, Eduardo

AU - Song, Xingzhi

AU - Zhang, Jianhua

AU - Kopetz, Scott

AU - Futreal, Andrew

AU - Wang, Y. Alan

AU - Kwong, Lawrence N.

AU - DePinho, Ronald A.

PY - 2017/2/15

Y1 - 2017/2/15

N2 - 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 (Krasmut) 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 Krasmut allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Krasmut signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of Krasmut-driven invasiveness. Genetic extinction of Krasmut resulted in specific elimination of the Krasmut subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Krasmut drives CRC invasion and maintenance of metastases.

AB - 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 (Krasmut) 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 Krasmut allele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activated Krasmut signaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator of Krasmut-driven invasiveness. Genetic extinction of Krasmut resulted in specific elimination of the Krasmut subpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease. This faithful CRC model provides genetic evidence that Krasmut drives CRC invasion and maintenance of metastases.

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Oncogenic Kras drives invasion and maintains metastases in colorectal cancer

Abstract

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ASJC Scopus subject areas

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