Metastasis is the most lethal feature of human cancers, but the molecular processes that govern metastatic spread are not well understood. One of the major obstacles in this crucial area of cancer research is the lack of faithful genetic de novo cancer model that results in regional and distant metastases. Xenograft models based on cancer cell lines cannot fully recapitulate the intricate interplay in the complex microenvironment of stromal and cancer cells. In addition, the necessity of using immuno-compromised mice for xenograft transplants precludes elucidation of the likely critical interaction between the primary cancer and the immune system in cancer progression. The Sharpless and Wong laboratories have recently generated de novo mouse lung cancer and melanoma models driven by activated oncogenic Kras and concurrent tumor suppressor Lkb1 loss that has a >60% penetrance of regional and distant metastases. We demonstrated that loss of Lkb1 function is crucial in the promotion of cancer invasion and metastasis and dissected the signaling pathways that are crucial to this process. We have now further improved this genetic model by incorporating a p53 mutant allele into the Lkb1/Kras mutant mice. Compound mutant mice with Kras driven lung cancer or melanoma that have concurrent Lkb1 and p53 loss have distant hematogenous metastases (100% penetrance), thus demonstrating distinct and separate tumor suppressor functions for Lkb1 and p53. Distant organs harboring metastases include lymph nodes, spleen, kidney, liver, bone and brain, recapitulating the full spectrum of metastatic sites observed in association with human lung cancers and melanoma. With this proposal, we wish to further characterize and refine these metastatic cancer models and incorporate in vivo non-invasive imaging markers (luciferase and enhanced green fluorescent protein) into these compound mutant mice to permit tracking of the location of micro- metastasis non-invasively using the latest in vivo non-invasive imaging techniques. These models will then be used to test targeted therapeutics that can kill these cancers and inhibit metastatic spread. With collaborators in the UNC Center for Integrative Chemical Biology and Drug Discovery, we will also develop small molecule tool compounds that will enhance metastatic behavior by inhibiting Lkb1 activity. These studies will yield important insights into primary and acquired resistance of these cancers to the various treatments to help facilitate better treatment strategies.

Public Health Relevance

Metastasis is the most lethal feature of cancer, but is poorly understood. Using faithful, genetically engineered models of lung cancer and melanoma, we will develop effective anti-metastasis therapies for in vivo use.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
Zip Code
Nakayama, Sohei; Sng, Natasha; Carretero, Julian et al. (2014) ?-catenin contributes to lung tumor development induced by EGFR mutations. Cancer Res 74:5891-902
Chen, Zhao; Akbay, Esra; Mikse, Oliver et al. (2014) Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 20:1204-11
Zhao, Ni; Wilkerson, Matthew D; Shah, Usman et al. (2014) Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer 86:255-61
Herter-Sprie, Grit S; Korideck, Houari; Christensen, Camilla L et al. (2014) Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models. Nat Commun 5:5870
Lovly, Christine M; McDonald, Nerina T; Chen, Heidi et al. (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027-34
Christensen, Camilla L; Kwiatkowski, Nicholas; Abraham, Brian J et al. (2014) Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26:909-22
Chen, Zhao; Fillmore, Christine M; Hammerman, Peter S et al. (2014) Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14:535-46
Chan, Keefe T; Asokan, Sreeja B; King, Samantha J et al. (2014) LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues. J Cell Biol 207:299-315
Akbay, Esra A; Moslehi, Javid; Christensen, Camilla L et al. (2014) D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev 28:479-90
Xu, Chunxiao; Fillmore, Christine M; Koyama, Shohei et al. (2014) Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25:590-604

Showing the most recent 10 out of 21 publications