Lab Research

Lab Research

 

Metastatic disease remains the predominant cause of death for cancer patients. Understanding the cellular and molecular mechanisms that regulate the metastatic process is critical to improved diagnosis and treatment. To this end, our laboratory research focuses on the functional identification of genes that specifically inhibit metastasis (e.g. metastasis-suppressor genes). During the past five years, our laboratory has led the effort to identify prostate cancer metastasis-suppressor genes on human chromosomes 17 and 12.

 

Chromosome 17 was chosen for our initial studies because its loss is associated with the progression of prostate cancers (1-3). We have recently identified the mitogen-activated protein kinase 4/stress-activated protein/Erk kinase 1/JNK-activating kinase 1 (MKK4/SEK1/JNKK1 hereafter referred to as MKK4) gene as a metastasis-suppressor gene encoded by chromosome 17 (4). This gene stands as one of five known metastasis suppressor genes (reviewed in 4). In animal models, MKK4 suppresses the growth of cancer cells at the metastatic site, a step known as metastatic colonization. MKK4 expression is decreased in high-grade primary human prostate cancers and metastases, supporting a role for its down-regulation in human disease. We are currently conducting mechanistic studies to discern how MKK4 functions to suppress metastasis.

 

In 1998, we initiated a second line of research on chromosome 12, since its loss is associated with the development of prostate cancer and bands 12pter-12q13 suppress tumorigenesis in human prostate cancer models (5). Initially, we identified a metastasis-suppressor activity encoded by an ~70 cM portion region and have now narrowed the region to an ~3 megabase (Mb) region on the q terminus. We are using positional cloning approaches to identify the metastasis-suppressor gene encoded by this region. Studies from animal models suggest that the candidate gene suppresses growth of the cells at the metastatic site. In contrast to MKK4, expression of the gene encoded by the ~3 Mb region results in death of the disseminated cells. This observation suggests that it works through a different mechanism than MKK4.

 

It is an exciting time in metastasis research. We are in the midst of a revolution in the way we view metastasis and the molecular determinants of metastatic growth. When we began this work, the prevailing view was that dissemination of cancer cells from the primary tumor was the rate-determining step for the development of metastases. Thus, our goal was to simply use the loss of metastasis-suppressor genes as a marker of metastatic ability. While this may still be of value, we now have evidence that metastasis-suppressor proteins specifically regulate the ability of cancer cells to grow at the secondary site. This represents a modification of the fundamental paradigm of metastasis research. Further, with the identification of a role for specific proteins with known biochemical functions, we can now conduct mechanistic studies to define signaling cascades regulating metastatic growth. Thus, we can take advantage of a wealth of biochemical information and are no longer confined to largely descriptive studies. We are working vigorously with our clinical collaborators to design strategies that will target cancer cell growth inhibition in the interval between tumor cell dissemination and metastatic colonization.