Oncogenic Kras drives invasion and maintains metastases in colorectal cancer
- Adam T. Boutin1,
- Wen-Ting Liao1,
- Melody Wang1,
- Soyoon Sarah Hwang1,
- Tatiana V. Karpinets2,
- Hannah Cheung2,
- Gerald C. Chu3,
- Shan Jiang2,
- Jian Hu1,
- Kyle Chang4,
- Eduardo Vilar4,5,
- Xingzhi Song3,
- Jianhua Zhang3,
- Scott Kopetz5,
- Andrew Futreal2,
- Y. Alan Wang1,
- Lawrence N. Kwong2,6 and
- Ronald A. DePinho1
- 1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
- 2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
- 3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
- 4Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
- 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
- 6Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
- Corresponding authors: rdepinho{at}mdanderson.org, lkwong{at}mdanderson.org, yalanwang{at}mdanderson.org
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.293449.116.
- Received November 5, 2016.
- Accepted February 15, 2017.
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