title: Context-Dependent Effects of Amplified MAPK Signaling during Lung Adenocarcinoma Initiation and Progression.
abstract: Expression of oncogenic KrasG12Dinitiates lung adenomas in a mitogen-activated protein kinase (MAPK) signal-dependent manner from only a subset of cell types in the adult mouse lung. Amplification of MAPK signaling is associated with progression to malignant adenocarcinomas, but whether this is a cause or a consequence of disease progression is not known. To better understand the effects of MAPK signaling downstream of KrasG12Dexpression, we capitalized on the ability of Braf inhibition to selectively amplify MAPK pathway signaling in KrasG12D-expressing epithelial cells. MAPK signal amplification indeed promoted the rapid progression of established adenomas to malignant adenocarcinomas. However, we observed, surprisingly, a greater number of overall tumor-initiating events after MAPK signal amplification, due to induced proliferation of cell types that are normally refractory to KrasG12D-induced transformation. Thus, MAPK signaling in the lung is thresholded not only during malignant progression but also at the moment of tumor initiation.
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cicchini
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Rosenthal Bldg., Philadelphia, PA 19104, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Buza
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA.
authors.forename: Kyra M
authors.initials: KM
authors.lastname: Sagal
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA.
authors.forename: A Andrea
authors.initials: AA
authors.lastname: Gudiel
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Rosenthal Bldg., Philadelphia, PA 19104, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Durham
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA. Electronic address: dfeldser@upenn.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Feldser
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Kras; MAPK; lung adenocarcinoma; p53