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

Publication date: 21 February 2017
Source:Cell Reports, Volume 18, Issue 8
Author(s): Michelle Cicchini, Elizabeth L. Buza, Kyra M. Sagal, A. Andrea Gudiel, Amy C. Durham, David M. Feldser
Expression of oncogenic Kras^G12D 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 Kras^G12D expression, we capitalized on the ability of Braf inhibition to selectively amplify MAPK pathway signaling in Kras^G12D-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 Kras^G12D-induced transformation. Thus, MAPK signaling in the lung is thresholded not only during malignant progression but also at the moment of tumor initiation.

Graphical abstract

Teaser

Cicchini et al. demonstrate that MAPK signaling is thresholded downstream of oncogenic Kras both in established lung adenomas progressing to malignancy and in diverse lung epithelial cell types to control tumor initiation. These thresholds underlie variations in cellular responses to oncogenic Kras in the lung.


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