The process of tumor dissemination or metastasis is an important aspect of clinical management of cancer. In most cases cancer patients with localized tumors have significantly better prognoses than those with disseminated tumors. The majority of cancer mortality has been associated with metastatic disease rather than the primary tumor. Since it has been estimated that 60-70% of patients have progressed to metastatic disease by the time of diagnosis better understanding of the factors leading to tumor dissemination is of vital importance. An enormous amount of research has been performed elucidating various components of this process. As a result a great deal is known about different molecules and pathways that are associated with metastatic progression, including activation of oncogenes, recruitment of metalloproteases, and motility factors. Metastasis-associated loss of heterozygosity has also been used as a tool to identify members of a class of genes known as the metastasis suppressors . To date eight members of this class of genes have been described: NM23, KISS1, KAI1, E-cadherin , MKK4, TIMPs, Maspin , BRMS1, RhoGDI2. Despite this wealth of information, the critical initiating events or molecular pathways for tumor dissemination remain unclear. Part of the difficulty unraveling the complexity of metastasis may be due to multiple converging pathways associated with malignant potential. Another confounding factor is likely to be genetic modulation of the efficiency of tumor dissemination. Identification of key regulatory components of the metastatic process would serve two functions. First, they might provide more accurate prognostic markers of potential metastatic progression in patients than the current standards. Second, they may provide insights into the critical events in tumor dissemination, potentially leading to additional avenues of research or the development of novel therapies. My laboratory uses animal models for gene discovery and/or test hypotheses that are difficult or impossible to do in human populations, including direct experimental testing of epidemiological correlations. The focus of my laboratory is a combined genetics and genomics approach to determine how constitutional genetic composition influences susceptibility to malignant progression. The model studied is the highly aggressive, metastatic transgenic mammary tumor FVB/N-TgN(MMTV-PyVT)634Mul mouse, which develops pulmonary metastatic lesions in ~85% of the animals by 100 days of age. By performing a breeding based strain survey, my laboratory demonstrated the first in vivo evidence that genetic background of the host is a major determinant of metastatic potential. Using quantitative trait genetic analysis of backcross or recombinant inbred mouse populations we subsequently mapped the location of at least two significant modifier genes and identified three other suggestive modifier genes. Currently my laboratory is applying both conventional mouse genetic and population-based strategies to attempt to identify and characterize the genes, pathways and polymorphisms that underlie the metastatic efficiency observed in the different genotypes. A two-prong strategy is being pursued. The first arm of the strategy is based on the conventional approach of developing interval specific congenic and subcongenic animals to generate a high-resolution mapping of the modifier genes followed by standard positional candidate strategies. While the conventional strategy has a high probability of success, it is a slow and laborious process that requires extensive animal breeding and manipulation. Therefore, in parallel with the conventional congenic based strategy, we are exploring alternative strategies for modifier candidate gene selection. For example, using latency as a phenotype in one of the backcrosses, we demonstrated that it is possible in some instances to select promising candidate genes based on known genetic interactions and bioinformatics based searches. The utility of this method was subsequently demonstrated by the identification of functional polymorphisms in both genes of interest, and by the in vivo replication of the latency phenotype in a transgenic experiment. We are currently pursuing this and other strategies to attempt to identify likely candidates for the metastasis efficiency genes, starting with the locus on chromosome 19. Finally, we plan to take advantage of the unique resources of mouse genetics to develop an integrated """"""""trans-ome"""""""", genome, transcriptome and proteome, characterization of mammary tumor metastasis. By exploring the expression patterns and protein levels and post-translational modification in the AKXD recombinant inbred mouse-mapping panel used for genetic mapping of the metastasis modifier genes, we should be able to explore the interface of genetic susceptibility to tumor dissemination with the intricate and interwoven biochemical pathways of the cell. We believe that this global approach to interrogating the metastatic process may yield novel insights into the complex and multiple pathways involved in this process, and potentially lead to exciting new strategies and targets for clinical intervention.

Agency
National Institute of Health (NIH)
Institute
Division of Cancer Epidemiology And Genetics (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CP010146-04
Application #
6954022
Study Section
(LPG)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hunter, Kent W; Amin, Ruhul; Deasy, Sarah et al. (2018) Genetic insights into the morass of metastatic heterogeneity. Nat Rev Cancer 18:211-223
Shukla, Anjali; Alsarraj, Jude; Hunter, Kent (2014) Understanding susceptibility to breast cancer metastasis: the genetic approach. Breast Cancer Manag 3:165-172
Hunter, Kent W (2012) Mouse models of cancer: does the strain matter? Nat Rev Cancer 12:144-9
Simmons, John K; Amlin-Van Schaick, Jessica C; Geiger, Thomas R et al. (2012) Mouse genetics 2011: meeting report. Mamm Genome 23:225-31
Alsarraj, Jude; Walker, Renard C; Webster, Joshua D et al. (2011) Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion. Cancer Res 71:3121-31
Hunter, Kent W; Alsarraj, Jude (2009) Gene expression profiles and breast cancer metastasis: a genetic perspective. Clin Exp Metastasis 26:497-503
Gordon, Ryan R; Hunter, Kent W; Sorensen, Peter et al. (2008) Genotype X diet interactions in mice predisposed to mammary cancer. I. Body weight and fat. Mamm Genome 19:163-78
Yang, Haiyan; Yu, Li-Rong; Yi, Ming et al. (2006) Parallel analysis of transcript and translation profiles: identification of metastasis-related signal pathways differentially regulated by drug and genetic modifications. J Proteome Res 5:1555-67
Hunter, Kent (2006) Host genetics influence tumour metastasis. Nat Rev Cancer 6:141-6
Hunter, Kent W; Crawford, Nigel P (2006) Germ line polymorphism in metastatic progression. Cancer Res 66:1251-4

Showing the most recent 10 out of 27 publications