Tumor suppressor pathways are frequently lost in human non-small lung cancers (NSCLC). Their repression furthermore has been linked to the reconstitution of self-renewal potential in fully developed cells and tissue stem cells. The identity of cell type(s) that initiate and maintain lung cancer has remained undefined;and even though a lung stem cell niche exists in the lung;its role in lung cancer tumorigenesis remains indeterminate. The objective of this study is to characterize cancer initiating cells in an oncogene inducible mouse lung tumor model and to elucidate the significance of tumor suppressors from the Cdkn2ab gene locus in lung cancer pathogenesis. We hypothesize that lung tissue stem cells expressing oncogene K-Ras in a Cdkn2ab deficient background will regain their ability to self-renew, lose cell polarity and initiate a malignant more aggressive NSCLC disease as compared to stem cells in the wild-type background.
In Aim 1, we will characterize tumor-initiating cells from an oncogene inducible mouse lung tumor model that are genetically labeled with green fluorescence protein (GFP). These cells will be isolated from wild-type and Cdkn2ab deficient backgrounds and characterized in tissue culture using immunofluorescence and western blot analysis.
In Aim 2, we will elucidate the effect of loss of tumor suppressors from the Cdkn2ab locus in NSCLC development in vivo by utilizing the oncogenic K-Ras inducible mouse lung tumor and xenograft mouse models. The characterization of cancer-initiating cells in this unique mouse model will provide an ideal platform to classify the molecular networks that determine lung cancer, and further portray these cells as a target for anti-cancer therapies.
Lung cancer is the leading cause of cancer related death in the United States. The proposed research will use a novel lung cancer mouse model in which tumor initiating cells have been genetically labeled for analysis. The characterization of these unique lung cells will provide a platform to elucidate the mechanisms leading to lung cancer and may ultimately lead to the development of lung cancer specific novel therapeutic drugs.
| Schuster, Katja; Venkateswaran, Niranjan; Rabellino, Andrea et al. (2014) Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis. Mol Cancer Res 12:912-23 |
