title: A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.
abstract: 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.
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675, München, Germany. roland.rad@lrz.tum.de
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.forename: Juan
authors.initials: J
authors.lastname: Cadiñanos
authors.forename: Lena
authors.initials: L
authors.lastname: Rad
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.forename: Alexander
authors.initials: A
authors.lastname: Strong
authors.forename: Lydia
authors.initials: L
authors.lastname: Kriegl
authors.forename: Fernando
authors.initials: F
authors.lastname: Constantino-Casas
authors.forename: Stefan
authors.initials: S
authors.lastname: Eser
authors.forename: Maren
authors.initials: M
authors.lastname: Hieber
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.forename: Stacey
authors.initials: S
authors.lastname: Price
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calvanese
authors.forename: Gary
authors.initials: G
authors.lastname: Hoffman
authors.forename: Hannes
authors.initials: H
authors.lastname: Ponstingl
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yusa
authors.forename: Carolyn
authors.initials: C
authors.lastname: Grove
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Vassiliou
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000209:etiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004354:Drug Screening Assays, Antitumor; D020935:MAP Kinase Signaling System; D051379:Mice; D053842:Microsatellite Instability; D009154:Mutation; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D060449:Wnt Signaling Pathway
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf