Send to

Choose Destination
Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4952-7. doi: 10.1073/pnas.1319963111. Epub 2014 Feb 28.

Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma.

Author information

Division of Molecular Genetics, Centre for Biomedical Genetics, and Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.


Much controversy surrounds the cell-of-origin of mutant K-Ras (K-RasG12D)-induced lung adenocarcinoma. To shed light on this issue, we have used technology that enables us to conditionally target K-RasG12D expression in Surfactant Protein C (SPC)(+) alveolar type 2 cells and in Clara cell antigen 10 (CC10)(+) Clara cells by use of cell-type-restricted recombinant Adeno-Cre viruses. Experiments were performed both in the presence and absence of the tumor suppressor gene p53, enabling us to assess what effect the cell-of-origin and the introduced genetic lesions have on the phenotypic characteristics of the resulting adenocarcinomas. We conclude that both SPC-expressing alveolar type 2 cells and CC10-expressing Clara cells have the ability to initiate malignant transformation following the introduction of these genetic alterations. The lungs of K-Ras(lox-Stop-lox-G12D/+) and K-Ras(lox-Stop-lox-G12D/+);tumor suppressor gene Trp53(F/F) mice infected with Adeno5-SPC-Cre and Adeno5-CC10-Cre viruses displayed differences in their tumor spectrum, indicating distinct cellular routes of tumor initiation. Moreover, using a multicolor Cre reporter line, we demonstrate that the resulting tumors arise from a clonal expansion of switched cells. Taken together, these results indicate that there are multiple cellular paths to K-RasG12D-induced adenocarcinoma and that the initiating cell influences the histopathological phenotype of the tumors that arise.


BASCs; NSCLC; bronchioalveolar stem cells; non small cell lung cancer

Comment in

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center