Determination of the cellular and molecular changes responsible for melanoma metastasis
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.
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 Candidate genes from the genomic screens above and from expression profiling experiments comparing transcripts from primary melanocytes with melanoma cell lines are being evaluated for their roles in cell survival, proliferation, migration, tumorigenesis, and metastasis. 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.
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 short 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 an inducible 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 are focused on the conditional knockout of the Pten tumor suppressor in the setting of Cdkn2a deficient mice.
Whole tissue xgal staining of tyrosinase-CreER and Rosa26-lacZ transgenic mouse skin. The blue staining at the base of the two hair follicles (bottom) reflects specific recombination in follicular melanocytes. The black arrow designates a melanocytic stem cell that has undergone recombination in the bulge region of the hair follicle.
Borowsky AD, Munn RJ, Galvez JJ, Cardiff RD, Ward JM, Morse HC 3rd, Kogan SC, Aldape KD, Louis DN, Bosenberg MW. Mouse models of human cancers Comp Med. 2004 Jun;54(3):258-70.
Sharpless NE, Kannan K, Xu J, Bosenberg MW, Chin L. Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo Oncogene. 2003 Aug 7;22(32):5055-9
Kannan K, Sharpless NE, Xu J, O\'Hagan RC, Bosenberg M, Chin L. Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1221-5.
You MJ, Castrillon DH, Bastian BC, O\'Hagan RC, Bosenberg MW, Parsons R, Chin L, DePinho RA. Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1455-60
Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans Nat Genet. 2001 Jun;28(2):155-9
* indicates equal contribution
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