Bosenberg Bio

Our laboratory is interested in understanding the process of tumor metastasis. The clinical importance of metastasis is unquestioned, as most of the mortality associated with cancer is the result of disseminated disease. Despite its importance, the current understanding of the complex process of metastasis is limited. Much of our work involves malignant melanoma, a metastatic and frequently lethal form skin cancer that arises from the pigment-producing cells of the skin. We are interested in several aspects of melanoma biology, including the genetic and phenotypic changes that result in melanoma formation and progression as described in more detail below.

Genomic changes in human melanoma

Widespread genomic instability is a hallmark of many types of cancers. Frequently this takes the form of chromosomal deletions, amplifications, or changes in chromosome number. Previous work using classical cytogenetics and comparative genomic hybridization have demonstrated a number of chromosomal sites that are recurrently altered in human melanoma. The ability to extract possible melanoma gene candidates from altered regions is limited by the 10 megabase resolution of comparative genomic hybridization. Preliminary data from more sensitive array comparative genomic hybridization and quantitative slot blotting experiments have revealed novel amplifications as small as 100 kilobases in size. Candidates from amplified/deleted regions are being evaluated by RT-PCR for gene expression and by functional assays.

Cell biology of candidate metastasis enhancers and suppressors

As candidate genes from the genomic screens as described become available, their roles in cell survival, proliferation, migration, tumorigenesis, and metastasis are being evaluated. Tyrosine kinase receptors have been shown on several occasions to induce malignant melanoma in mouse and fish models and several receptor tyrosine kinases are being evaluated to determine what role they play in human melanoma. Gene products in the phosphatidylinositol 3-kinase (PI3-K) pathway, which is stimulated by some receptor tyrosine kinases, are also being examined to determine if they contribute to melanoma formation and metastasis.

Mouse models of metastatic malignant melanoma

We are in the process of generating improved mouse models of melanoma. Some current mouse models of malignant melanoma have a high penetrance and low latency, but tend to arise deeper in the skin than human melanoma, and do not metastasize. Our goal is to develop mouse models of melanoma that have a high incidence of metastatic melanoma and have a low incidence of non-melanoma tumors such lymphomas and sarcomas. These models will increase our understanding of the metastatic process and may also be used to evaluate potential pharmaceutical agents that prevent metastasis. One mouse model being developed involves use of the Cre-lox recombinase system to generate conditional knockout mice. Cre recombinase expression is directed by the melanocyte-specific tyrosinase promoter/enhancer. Alleles of genes containing loxP sequences recognized by Cre will be recombined in melanocytes, resulting in deletion of the DNA segment between the loxP sites and loss of gene function. Initial experiments will focus on the conditional knockout of the Pten tumor suppressor in the setting of Cdkn2a deficient mice.