TY - JOUR
T1 - A Genetic Progression Model of BrafV600E-Induced Intestinal Tumorigenesis Reveals Targets for Therapeutic Intervention
AU - Rad, Roland
AU - Cadiñanos, Juan
AU - Rad, Lena
AU - Varela, Ignacio
AU - Strong, Alexander
AU - Kriegl, Lydia
AU - Constantino-Casas, Fernando
AU - Eser, Stefan
AU - Hieber, Maren
AU - Seidler, Barbara
AU - Price, Stacey
AU - Fraga, Mario F.
AU - Calvanese, Vincenzo
AU - Hoffman, Gary
AU - Ponstingl, Hannes
AU - Schneider, Günter
AU - Yusa, Kosuke
AU - Grove, Carolyn
AU - Schmid, Roland M.
AU - Wang, Wei
AU - Vassiliou, George
AU - Kirchner, Thomas
AU - McDermott, Ultan
AU - Liu, Pentao
AU - Saur, Dieter
AU - Bradley, Allan
N1 - Funding Information:
We thank the research support facility team, Tatiana Schmid, and Magdalena Zukowska, for excellent technical assistance. Anton Berns is gratefully acknowledged for critical discussions, and Melanie Kucherlapati is acknowledged for providing Msh2-deficint tumor DNA. The work was supported by the Wellcome Trust (to A.B.) and the Helmholtz Gemeinschaft (PCCC Consortium; to R.R. and D.S.). R.R., J.C., and I.V. were supported by fellowships from the Deutsche Forschungsgemeinschaft, FEBS, and International Human Frontiers Science Program Organization, respectively, during part of this work.
PY - 2013/7/8
Y1 - 2013/7/8
N2 - We show that BRAFV600E 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 BrafV600E 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.
AB - We show that BRAFV600E 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 BrafV600E 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.
UR - http://www.scopus.com/inward/record.url?scp=84880020762&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2013.05.014
DO - 10.1016/j.ccr.2013.05.014
M3 - Article
C2 - 23845441
AN - SCOPUS:84880020762
SN - 1535-6108
VL - 24
SP - 15
EP - 29
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -
