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Cell Rep. 2017 Feb 21;18(8):1958-1969. doi: 10.1016/j.celrep.2017.01.069.

Context-Dependent Effects of Amplified MAPK Signaling during Lung Adenocarcinoma Initiation and Progression.

Author information

1
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.
2
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Rosenthal Bldg., Philadelphia, PA 19104, USA.
3
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.

Abstract

Expression of oncogenic KrasG12D initiates 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 KrasG12D expression, 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.

KEYWORDS:

Kras; MAPK; lung adenocarcinoma; p53

PMID:
28228261
PMCID:
PMC5405440
DOI:
10.1016/j.celrep.2017.01.069
[Indexed for MEDLINE]
Free PMC Article

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