Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer

Samanthi A. Perera, Richard S. Maser, Huili Xia, Kate McNamara, Alexei Protopopov, Liang Chen, Aram F.hezel, Carla F. Kim, Roderick T. Bronson, Diego H. Castrillon, Lynda Chin, Nabeel Bardeesy, Ronald A. DePinho, Kwok Kin Wong

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Current mouse models of lung cancer recapitulate signature genetic lesions and some phenotypic features of human lung cancer. However, because mice have long telomeres, models to date do not recapitulate the aspects of lung carcinogenesis - telomere attrition and the genomic instability that ensues - believed to serve as key mechanisms driving lung tumor initiation and progression. To explore the contributions of telomere dysfunction to lung cancer progression, we combined a telomerase catalytic subunit (mTerc) mutation with the well-characterized K-rasG12D mouse lung cancer model. K-rasG12D mTerc-/- mice with telomere dysfunction but intact p53 exhibited increased lung epithelial apoptosis, delayed tumor formation and increased life span relative to K-rasG12D mTerc-/- mice with intact telomere function. This demonstrates that by itself, telomere dysfunction acts in a tumor-suppressive mechanism. Introduction of a heterozygous p53 mutation exerted a marked histopathological, biological and genomic impact. K-rasG12D mTerc-/- P53+/- mice developed aggressive tumors with more chromosomal instabilities and high metastatic potential, leading to decreased overall survival. Thus, we have generated a murine model that more faithfully recapitulates key aspects of the human disease. Furthermore, these findings clearly demonstrate (in an in vivo model system) the dual nature of telomere shortening as both a tumor-suppressive and tumor-promoting mechanism in lung cancer, dependent on p53 status.

Original languageEnglish (US)
Pages (from-to)747-753
Number of pages7
JournalCarcinogenesis
Volume29
Issue number4
DOIs
StatePublished - Apr 2008

ASJC Scopus subject areas

  • Cancer Research

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    Perera, S. A., Maser, R. S., Xia, H., McNamara, K., Protopopov, A., Chen, L., F.hezel, A., Kim, C. F., Bronson, R. T., Castrillon, D. H., Chin, L., Bardeesy, N., DePinho, R. A., & Wong, K. K. (2008). Telomere dysfunction promotes genome instability and metastatic potential in a K-ras p53 mouse model of lung cancer. Carcinogenesis, 29(4), 747-753. https://doi.org/10.1093/carcin/bgn050