Research Interests: Cancer Genetics in the Zebrafish
The major goal of our lab is to understand the earliest steps in cancer at a molecular level. Our focus is on defining novel cancer genes and on understanding the developmental biology of tumors. To accomplish this, we have turned to the zebrafish system. The zebrafish is a wonderful complement to mouse, fly, worm and other disease models. The fish produce large numbers of progeny weekly and are easily maintained, allowing us to take large-scale, genome-wide approaches. The transparent embryos develop external to the mother and are accessible to manipulation with transgenic or antisense approaches. At the same time, fish have true vertebrate anatomy and physiology, and are susceptible to the same tumors as are humans, making them an excellent cancer model.
•Cancer Susceptibility. In previous work, we carried out a large-scale screen that identified mutations affecting cell proliferation in zebrafish embryos. Importantly, several of these mutations cause increased cancers in adult heterozygotes. One of the mutants, crash&burn, has a mutation in the B-myb transcription factor. Working with the mutant embryos we demonstrated a genetic pathway through B-myb and cyclin B. Defects in this pathway lead to mitotic abnormalities and aneuploidy, both hallmarks of cancer cells. This pathway appears to be recapitulated in human cancers, and may signal a p53-independent mode of tumorigenesis. Another mutant from the screen, cease&desist, carries a mutation in separase, the protease regulating sister-chromatid cohesion. Loss of separase causes a high degree of genomic instability, and heterozygotes show markedly increased susceptibility to epithelial cancers. In humans, genomic instability is particularly prevalent in epithelial tumors, suggesting that the cease&desist mutant will provide a novel model for the most common types of human cancer.
•DNA Damage Response. A cell?s DNA is under constant assault from the environment, and the pathways by which cells detect and repair damage to the DNA are vital for preserving the stability of the genome. Deficiencies in these pathways lead to inherited cancer syndromes. Furthermore, DNA damage is the central mechanism for both the efficacy and the undesirable side effects of chemotherapy and radiation therapy, making this one of the central pathways in cancer biology. We are beginning to apply the power of zebrafish genetics to understanding the DNA damage response. In a pilot screen, we have isolated several mutants that lack components of the damage response. We are also interested in using high-throughput approaches to identify novel compounds that act as radioprotectants or as radiosensitizers for use in the clinical setting.
•Testicular Cancer. Testicular Germ Cell Tumor (TGCT) is the most common cancer in men aged 20-40 and is increasing dramatically in incidence worldwide. While TGCTs are generally sensitive to chemo- and radiotherapy, the reasons underlying this sensitivity are unknown, and a better understanding of the causes and biology of TGCT could therefore have wide implications for cancer therapy as a whole. Furthermore, the long-term toxicities of chemotherapy and radiation are substantial, underscoring the importance of identifying new molecular pathways for targeted therapy. Recently, we have discovered a mutation that causes heritable testicular cancer in zebrafish. The tumors display histopathology and radiation sensitivity very similar to human testicular cancer, and we are attempting to clone the mutant gene through analysis of linked markers in affected kindreds. While human testicular cancer is clearly a genetic disease, the affected genes have not been identified, and animal models are lacking. Thus the zebrafish model will provide a platform for testing new therapeutic approaches to testicular cancer. Additionally, the intimate association of testicular cancer and normal germ-cell developmental pathways means that insight into testicular carcinogenesis may also have implications for stem cell biology and infertility.
RESEARCH INTERESTS
Zebrafish
Cancer Genetics
Animal Models of Cancer
DNA Damage Response
Testicular Cancer
RECENT PUBLICATIONS
Shepard JL, Amatruda JF, Finkelstein D, Ziai J, Finley KR, Stern HM, Chiang K, Hersey C, Barut B, Freeman JL, Lee C, Glickman JN, Kutok JL, Aster JC, Zon LI., "A mutation in separase causes genome instability and increased susceptibility to epithelial cancer." Genes & Development, 21(1):55-59, January 2007
Stern HM, Murphey RD, Shepard JL, Amatruda JF, Straub C, Pfaff KL, Tallarico JA, King RW and Zon LI, "Persynthamide suppresses bmyb-associated cell cycle defects via the intra-S checkpoint." Nature Chemical Biology, 1(7):366-70, December 2005
Shepard JL*, Amatruda JF*, Stern HM, Finkelstein D, Ziai J, Finley KR, Pfaff KL, Hersey C, Zhou Y, Freedman M, Lee C, Spitsbergen J, Neuberg D, Glickman JN, Kutok JL, Aster J and Zon LI (*equal contribution), "A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility." Proc Natl Acad Sci, 102(37):13194-9, September 2005
Patton EE, Widlund H, Kutok J, Kopani K, Amatruda JF, Murphey RD, Berghamans S, Mayhall E, Traver D, Fletcher CDM, Aster J, Granter S, Look AT, Lee C, Fisher DE, Zon LI, "BRAF mutations are sufficient to promote nevi formation, and cooperate with p53 in the genesis of melanoma" Current Biology, 15:249-254, February 2005
Amatruda, JF, Shepard JL, Stern HM, Zon, LI, "Zebrafish as a Cancer Model System" Cancer Cell, 1:216-218, 2002
SIGNIFICANT PUBLICATIONS
Shepard JL*, Amatruda JF*, Stern HM, Finkelstein D, Ziai J, Finley KR, Pfaff KL, Hersey C, Zhou Y, Freedman M, Lee C, Spitsbergen J, Neuberg D, Glickman JN, Kutok JL, Aster J and Zon LI (*equal contribution), "A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility" Proc Natl Acad Sci, in press September 2005
Patton EE, Widlund H, Kutok J, Kopani K, Amatruda JF, Murphey RD, Berghamans S, Mayhall E, Traver D, Fletcher CDM, Aster J, Granter S, Look AT, Lee C, Fisher DE, Zon LI, "BRAF mutations are sufficient to promote nevi formation, and cooperate with p53 in the genesis of melanoma" Current Biology, 15:249-254, February 2005
Amatruda JF, Cooper JA, "Effect of Null Mutations and Overexpression of Capping Protein on Morphogenesis, Actin Distribution and Polarized Secretion in Yeast" J Cell Biol, 119:11151-1162, 1992
Amatruda, JF, Cannon JF, Tatchell K, Hug C, Cooper JA, "Disruption of the actin cytoskeleton in yeast capping protein mutants" Nature, 344:352-354, 1990
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