title: EGF receptor is required for KRAS-induced pancreatic tumorigenesis.
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.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Ardito
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Grüner
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Takeuchi
authors.forename: Clara
authors.initials: C
authors.lastname: Lubeseder-Martellato
authors.forename: Nicole
authors.initials: N
authors.lastname: Teichmann
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Delgiorno
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Carpenter
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Halbrook
authors.forename: Jason C
authors.initials: JC
authors.lastname: Hall
authors.forename: Debjani
authors.initials: D
authors.lastname: Pal
authors.forename: Thomas
authors.initials: T
authors.lastname: Briel
authors.forename: Alexander
authors.initials: A
authors.lastname: Herner
authors.forename: Marija
authors.initials: M
authors.lastname: Trajkovic-Arsic
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Geou-Yarh
authors.initials: GY
authors.lastname: Liou
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Murray
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wilson
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Raines
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)