Analysis of Lung Tumor Initiation and Progression Using Conditional Expression of Oncogenic K-ras

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2001 Dec 26

PMID 11751630

Citations 1140

Authors

E L Jackson

N Willis

K Mercer

R T Bronson

D Crowley

R Montoya

T Jacks

D A Tuveson

Affiliations

Soon will be listed here.

Abstract

Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.

Citing Articles

Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system.

Jang G, Park R, Esteva E, Hsu P, Feng J, Upadhaya S J Exp Med. 2025; 222(6).

PMID: 40072317 PMC: 11899982. DOI: 10.1084/jem.20240587.

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Perelli L, Zhang L, Mangiameli S, Giannese F, Mahadevan K, Peng F Nature. 2025; .

PMID: 40044861 DOI: 10.1038/s41586-025-08671-2.

Methodology of murine lung cancer mimics clinical lung adenocarcinoma progression and metastasis.

Kim E, Kim E, Knott E, Wang Y, Chen C, Conejo-Garcia J Sci Rep. 2025; 15(1):7127.

PMID: 40021683 PMC: 11871348. DOI: 10.1038/s41598-025-90344-1.

Muller M, May S, Hall H, Kendall T, McGarry L, Blukacz L Nature. 2025; .

PMID: 39972137 DOI: 10.1038/s41586-025-08585-z.

A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development.

Schneider A, Koppe C, Crouchet E, Papargyriou A, Singer M, Buttner V Nat Commun. 2025; 16(1):1765.

PMID: 39971907 PMC: 11839950. DOI: 10.1038/s41467-025-56493-7.

References

Mason R, Kalina M, Nielsen L, Malkinson A, Shannon J . Surfactant protein C expression in urethane-induced murine pulmonary tumors. Am J Pathol. 2000; 156(1):175-82. PMC: 1868632. DOI: 10.1016/S0002-9440(10)64717-7. View

Kerr K . Pulmonary preinvasive neoplasia. J Clin Pathol. 2001; 54(4):257-71. PMC: 1731391. DOI: 10.1136/jcp.54.4.257. View

Johnson L, Mercer K, Greenbaum D, Bronson R, Crowley D, Tuveson D . Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001; 410(6832):1111-6. DOI: 10.1038/35074129. View

Dermer G . Origin of bronchioloalveolar carcinoma and peripheral bronchial adenocarcinoma. Cancer. 1982; 49(5):881-7. DOI: 10.1002/1097-0142(19820301)49:5<881::aid-cncr2820490511>3.0.co;2-7. View

Plopper C, Alley J, Serabjitsingh C, Philpot R . Cytodifferentiation of the nonciliated bronchiolar epithelial (Clara) cell during rabbit lung maturation: an ultrastructural and morphometric study. Am J Anat. 1983; 167(3):329-57. DOI: 10.1002/aja.1001670305. View

Kobayashi T, Tsuda H, Noguchi M, Hirohashi S, Shimosato Y, Goya T . Association of point mutation in c-Ki-ras oncogene in lung adenocarcinoma with particular reference to cytologic subtypes. Cancer. 1990; 66(2):289-94. DOI: 10.1002/1097-0142(19900715)66:2<289::aid-cncr2820660216>3.0.co;2-6. View

Thaete L, Malkinson A . Cells of origin of primary pulmonary neoplasms in mice: morphologic and histochemical studies. Exp Lung Res. 1991; 17(2):219-28. DOI: 10.3109/01902149109064413. View

Lakso M, Sauer B, Mosinger Jr B, Lee E, Manning R, Yu S . Targeted oncogene activation by site-specific recombination in transgenic mice. Proc Natl Acad Sci U S A. 1992; 89(14):6232-6. PMC: 49474. DOI: 10.1073/pnas.89.14.6232. View

Wikenheiser K, Clark J, Linnoila R, STAHLMAN M, Whitsett J . Simian virus 40 large T antigen directed by transcriptional elements of the human surfactant protein C gene produces pulmonary adenocarcinomas in transgenic mice. Cancer Res. 1992; 52(19):5342-52. View

10.

HAMMOND W, Benfield J, TEPLITZ R, Dijkman J . Expression of alveolar type II cell markers in acinar adenocarcinomas and adenoid cystic carcinomas arising from segmental bronchi. A study in a heterotopic bronchogenic carcinoma model in dogs. Am J Pathol. 1993; 142(4):1251-64. PMC: 1886860. View

11.

Mori M, Chiba R, Takahashi T . Atypical adenomatous hyperplasia of the lung and its differentiation from adenocarcinoma. Characterization of atypical cells by morphometry and multivariate cluster analysis. Cancer. 1993; 72(8):2331-40. DOI: 10.1002/1097-0142(19931015)72:8<2331::aid-cncr2820720808>3.0.co;2-e. View

12.

Wuenschell C, Sunday M, Singh G, Minoo P, Slavkin H, Warburton D . Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages. J Histochem Cytochem. 1996; 44(2):113-23. DOI: 10.1177/44.2.8609367. View

13.

Westra W, Baas I, Hruban R, Askin F, Wilson K, Offerhaus G . K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res. 1996; 56(9):2224-8. View

14.

Magdaleno S, Wang G, Mireles V, Ray M, Finegold M, Demayo F . Cyclin-dependent kinase inhibitor expression in pulmonary Clara cells transformed with SV40 large T antigen in transgenic mice. Cell Growth Differ. 1997; 8(2):145-55. View

15.

Benfield J, van Krieken J, Dijkman J . The alveolar type II cell is a pluripotential stem cell in the genesis of human adenocarcinomas and squamous cell carcinomas. Histol Histopathol. 1997; 12(2):319-36. View

16.

Wikenheiser K, Whitsett J . Tumor progression and cellular differentiation of pulmonary adenocarcinomas in SV40 large T antigen transgenic mice. Am J Respir Cell Mol Biol. 1997; 16(6):713-23. DOI: 10.1165/ajrcmb.16.6.9191473. View

17.

Johnson L, Greenbaum D, Cichowski K, Mercer K, Murphy E, Schmitt E . K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 1997; 11(19):2468-81. PMC: 316567. DOI: 10.1101/gad.11.19.2468. View

18.

Kitamura H, Kameda Y, Ito T, Hayashi H, Nakamura N, Nakatani Y . Cytodifferentiation of atypical adenomatous hyperplasia and bronchioloalveolar lung carcinoma: immunohistochemical and ultrastructural studies. Virchows Arch. 1998; 431(6):415-24. DOI: 10.1007/s004280050118. View

19.

Fasbender A, Lee J, Walters R, Moninger T, Zabner J, Welsh M . Incorporation of adenovirus in calcium phosphate precipitates enhances gene transfer to airway epithelia in vitro and in vivo. J Clin Invest. 1998; 102(1):184-93. PMC: 509080. DOI: 10.1172/JCI2732. View

20.

Malkinson A . Molecular comparison of human and mouse pulmonary adenocarcinomas. Exp Lung Res. 1998; 24(4):541-55. DOI: 10.3109/01902149809087385. View