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A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.

Rad R, Cadiñanos J, Rad L, Varela I, Strong A, Kriegl L, Constantino-Casas F, Eser S, Hieber M, Seidler B, Price S, Fraga MF, Calvanese V, Hoffman G, Ponstingl H, Schneider G, Yusa K, Grove C, Schmid RM, Wang W, Vassiliou G, Kirchner T, McDermott U, Liu P, Saur D, Bradley A
Cancer Cell. 2013 24 (1): 15-29

PMID: 23845441 · PMCID: PMC3706745 · DOI:10.1016/j.ccr.2013.05.014

We show that BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf(V600E) expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (15)

Animals Cell Transformation, Neoplastic Colorectal Neoplasms Cyclin-Dependent Kinase Inhibitor p16 Drug Screening Assays, Antitumor MAP Kinase Signaling System Mice Microsatellite Instability Mutation Neoplasm Invasiveness Neoplasm Proteins Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins B-raf Tumor Suppressor Protein p53 Wnt Signaling Pathway

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