Our Science – Hunter Website
Kent W. Hunter, Ph.D.
The process of metastasis is of great importance to the clinical management of cancer because most cancer deaths are attributable to disseminated disease rather than the primary tumor. To better manage this critical clinical aspect of cancer it is necessary to gain a better understanding of the factors that lead to metastasis. To date the majority of metastasis research has focused on somatic alterations in tumor cells. However, in spite of decades of research and the identification of a large number of tumor cell-autonomous metastasis-associated genes, the process is still largely a mystery. Furthermore, it is still unclear whether metastasis is driven primarily by somatic events in the tumor or subject to functional variation at the level of the whole organism. Knowledge of this latter component may be critically important to the early identification of patients at risk for metastasis, which might alter their management and improve their prognosis. The major goal of my laboratory is therefore to complement the existing and historic investigations of the tumor genome by characterizing the previously unexplored realm of the impact of constitutional genetic polymorphism on metastatic progression.
To accomplish this, our laboratory initiated an investigation into the effects of constitutional genetic polymorphism on metastatic efficiency. Using the polyoma middle-T transgene-induced mouse mammary tumor model, we demonstrated that the genetic background upon which a tumor arose significantly influenced the ability of the tumor to form pulmonary metastases. Quantitative trait genetic mapping analysis revealed the presence of a metastasis efficiency locus, designated Mtes1, on proximal mouse chromosome 19 in a 10 megabase region orthologous to human chromosome 11q12-13. Subsequently, using haplotype mapping and in vitro and in vivo assays, we have identified the signal transduction gene Sipa1 as a probable candidate for the Mtes1 locus. These results, to the best of our knowledge, are the first evidence suggesting that constitutional polymorphism, in addition to somatic mutation within the tumor epithelium, plays a significant role in determining metastatic efficiency. The existence of these constitutional genetic variants may have profound implications for cancer prognosis and clinical management by permitting improved patient risk stratification and potentially subsequent enrollment in prophylactic anti-metastatic therapeutic regimens.
Using this evidence, we have focused our recent efforts on an integrated systems strategy to identify new Mtes candidate loci. Results from expression array experiments in our laboratory as well as others have demonstrated that extracellular matrix (ECM) associated genes are almost universally implicated in metastasis predictive gene signature profiles. Examination of the genetic factors influencing expression (eQTLs) of these genes revealed a correlation of ECM eQTLs and the Mtes loci suggesting a possible causal link between the two sets of QTLs. We are currently combining a variety of methodologies to investigate genes of interest. Once interesting candidate genes are identified, further characterization will be performed to gain insights into the mechanisms and role of each gene in the metastatic process.
This page was last updated on 2/20/2013.