TY - JOUR
T1 - EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis
AU - Ardito, Christine M.
AU - Grüner, Barbara M.
AU - Takeuchi, Kenneth K.
AU - Lubeseder-Martellato, Clara
AU - Teichmann, Nicole
AU - Mazur, Pawel K.
AU - DelGiorno, Kathleen E.
AU - Carpenter, Eileen S.
AU - Halbrook, Christopher J.
AU - Hall, Jason C.
AU - Pal, Debjani
AU - Briel, Thomas
AU - Herner, Alexander
AU - Trajkovic-Arsic, Marija
AU - Sipos, Bence
AU - Liou, Geou Yarh
AU - Storz, Peter
AU - Murray, Nicole R.
AU - Threadgill, David W.
AU - Sibilia, Maria
AU - Washington, M. Kay
AU - Wilson, Carole L.
AU - Schmid, Roland M.
AU - Raines, Elaine W.
AU - Crawford, Howard C.
AU - Siveke, Jens T.
N1 - Funding Information:
This work was supported by a VA Merit Award, the Knapp Chair for Pancreatic Cancer Research, and National Institutes of Health (NIH) Grants R01CA159222 and R03CA129579 to H.C.C.; NIH Grants P01HL018645 and R01HL067267 to E.W.R.; a pilot and feasibility award from the University of Washington Nutrition and Obesity Center, Grant DK035816 to C.L.W.; grants from the Austrian Science Fund ([FWF] W1212), the EC Program (LSHC-CT-2006-037731), and the GEN-AU Program “Austromouse” (GZ200.147/1-VI/1a/2006 and 820966) to M.S.; Grants R01CA092479 and P50CA106991 to D.W.T.; Grant R01CA140290 to N.R.M.; Grant R01CA140182 to P.S.; Grant P50CA102701 to the Mayo Clinic Pancreatic Cancer SPORE; Grant P50CA095103 for the Vanderbilt University Medical Center GI Spore Tissue Core; Deutsche Krebshilfe (Grant 109992 to J.T.S.), the German Federal Ministry of Education and Research (National Genomic Research Network [NGFN-Plus], 01GS08115 to J.T.S. and R.M.S.); and the German Research Foundation (SFB824/C4 to J.T.S.). TROMAIII antibody, developed by Rolf Kemmler, was obtained from the Developmental Studies Hybridoma Bank, developed under the auspices of the National Institute of Child Health and Human Development, and maintained by The University of Iowa, Department of Biology, Iowa City, IA.
PY - 2012/9/11
Y1 - 2012/9/11
N2 - Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
AB - Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.
UR - http://www.scopus.com/inward/record.url?scp=84866007085&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2012.07.024
DO - 10.1016/j.ccr.2012.07.024
M3 - Article
C2 - 22975374
AN - SCOPUS:84866007085
SN - 1535-6108
VL - 22
SP - 304
EP - 317
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -
