Details

Autor(en) / Beteiligte

• Ardito, Christine M.
• Grüner, Barbara M.
• Takeuchi, Kenneth K.
• Lubeseder-Martellato, Clara
• Teichmann, Nicole
• Mazur, Pawel K.
• DelGiorno, Kathleen E.
• Carpenter, Eileen S.
• Halbrook, Christopher J.
• Hall, Jason C.
• Pal, Debjani
• Briel, Thomas
• Herner, Alexander
• Trajkovic-Arsic, Marija
• Sipos, Bence
• Liou, Geou-Yarh
• Storz, Peter
• Murray, Nicole R.
• Threadgill, David W.
• Sibilia, Maria
• Washington, M. Kay
• Wilson, Carole L.
• Schmid, Roland M.
• Raines, Elaine W.
• Crawford, Howard C.
• Siveke, Jens T.

Titel

EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis

Ist Teil von

• Cancer cell, 2012-09, Vol.22 (3), p.304-317

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. ► KRAS-mediated tumorigenesis is inhibited in pancreatic Egfr and Adam17 knockouts ► Pancreatitis-induced tumors are blocked by pancreatic Egfr or Adam17 ablation ► Pancreatic Egfr and Adam17 knockouts resist metaplasia in vitro and in vivo ► KRAS requires EGFR to robustly activate ERK, which is necessary for tumorigenesis