1. EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis
- Author
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Carole L. Wilson, Debjani Pal, Clara Lubeseder-Martellato, Kathleen E. DelGiorno, Jason C. Hall, Christopher J. Halbrook, Peter Storz, Howard C. Crawford, Thomas Briel, Christine M. Ardito, Jens T. Siveke, David W. Threadgill, M. Kay Washington, Barbara M. Grüner, Nicole Teichmann, Marija Trajkovic-Arsic, Eileen S. Carpenter, Nicole R. Murray, Alexander Herner, Elaine W. Raines, Maria Sibilia, Kenneth K. Takeuchi, Pawel K. Mazur, Geou Yarh Liou, Roland M. Schmid, and Bence Sipos
- Subjects
MAPK/ERK pathway ,Cancer Research ,Transgene ,Mutant ,Medizin ,Mice, Transgenic ,Biology ,ADAM17 Protein ,medicine.disease_cause ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptor ,Extracellular Signal-Regulated MAP Kinases ,Pancreas ,030304 developmental biology ,0303 health sciences ,Oncogene ,Epithelial Cells ,Cell Biology ,Sheddase ,digestive system diseases ,ErbB Receptors ,Pancreatic Neoplasms ,ADAM Proteins ,Cell Transformation, Neoplastic ,Genes, ras ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,KRAS ,Carcinogenesis ,Carcinoma, Pancreatic Ductal - Abstract
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. © 2012 Elsevier Inc..
- Published
- 2012
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