title: OncogenicKrasdrives 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 theKRASgene. To understand the role of oncogenicKRASin CRC, we engineered a mouse model of metastatic CRC that harbors an inducible oncogenicKrasallele (Krasmut) and conditional null alleles ofApcandTrp53(iKAP). The iKAP model recapitulates tumor progression from adenoma through metastases. Whole-exome sequencing revealed that theKrasmutallele was heterogenous in primary tumors yet homogenous in metastases, a pattern consistent with activatedKrasmutsignaling being a driver of progression to metastasis. System-level and functional analyses revealed the TGF-β pathway as a key mediator ofKrasmut-driven invasiveness. Genetic extinction ofKrasmutresulted in specific elimination of theKrasmutsubpopulation in primary and metastatic tumors, leading to apoptotic elimination of advanced invasive and metastatic disease.This faithful CRC model provides genetic evidence thatKrasmutdrives CRC invasion and maintenance of metastases.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Boutin
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liao
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Soyoon Sarah
authors.initials: SS
authors.lastname: Hwang
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Karpinets
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Cheung
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Chang
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Vilar
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Song
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Futreal
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Apc; Kras; P53; colorectal cancer; invasion; metastasis