The Cheng lab is interested in fundamental genetic and molecular mechanisms that cause cancer, basic mechanisms underlying the relationship between human skin pigmentation and cancer, and contributing to web-based infrastructures for science, education, and public service. Our laboratory pioneered genetic screens in zebrafish to find new genes related to cancer. Our screens targeted two processes affected in cancer: mutation and cell differentiation. We are producing an on-line, high-resolution, full-lifespan atlas of the zebrafish that will be integrated with other anatomical web sites of zebrafish, other model organisms, and other disciplines. Collaboratively, we are developing 2D and 3D image informatics tools for systems biology and medicine, and new methods for X-ray based high resolution 3D imaging at cellular and subcellular resolutions.
We have actively encouraged other laboratories to use the power of zebrafish functional genomics to study the functions of genes in the context of the whole organism, and in development. We have developed the idea that zebrafish functional genomics is a powerful tool for the dissection of the functions of each of the possible combinations of subunit isoforms of multimeric proteins. A detailed discussion of this functional genomics approach, being pursued in collaboration with Drs. Robert Levenson (Na/K ATPase; Department of Pharmacology, Penn State College of Medicine) and Janet Robishaw (heterotrimeric G proteins, Weis Center for Research, Danville, PA) has been recently reviewed (See Cheng, Levenson and Robishaw, 2003, below). We have also participated in Glenn Gerhard‘s pioneering work to define the lifespan of the zebrafish, to set the stage for its use in the study of aging (see publications below with Gerhard, of the Weis Center for Research in Danville).
Our understanding of European skin is already partially delineated: in 2005, our lab uncovered one of the most pervasive genetic mutations (SLC24A5) that contribute to the light color of European skin. Europeans also carry a 10 to 20-fold increase in melanoma susceptibility (one of the deadliest forms of skin cancer) when compared to Africans. Surprisingly, East Asians, unlike Europeans, carry a seemingly unusual protection against melanoma: their incidences of disease are similar to those of Africans, despite their relatively light skin color due to yet unknown genetic pathways. To understand this misnomer, the first step is to identify these East Asian-specific genetic mutations.
Answers to the basic question of how and why gene function is lost in somatic tissues will contribute to our understanding of aging and some forms of human disease, including cancer. Those mutations play a key role in the evolution of killer cancer cells from the originally normal ones of cancer victims, and also the evolution of resistant cancer cells after treatment. The tendency to mutate one’s DNA can be called genetic instability or genomic instability, and the phenotype of elevated mutation rate is called mutator phenotype. In order to discover new vertebrate genes that control mutation, we have used the zebrafish (Danio rerio) to generate mutants that show elevated rates of somatic (body cell) mutation. In this screen, we scored for increased somatic loss of heterozygosity at a marker locus, golden. We expect genetic instability to be caused by deficiencies in any of a number of functions, including chromosome segregation, recombination, and DNA repair. We are studying the characteristics of mutants, including the ability of the mutations to significantly increase cancer susceptibility, and are engaged in the positional cloning of these mutations. Insights gained from these studies will increase our understanding of the molecular forces that drive evolution and may suggest new ways to fight cancer. Since these genomic instability (“gin”) mutants tend to develop cancer, they represent an animal model for human genetic syndromes that predispose to cancer, and may promote the detection of environmental mutagens. This novel approach to the study of genetic instability was sponsored originally by the Jake Gittlen Memorial Golf Tournament, American Cancer Society, and the National Science Foundation.
Our lab is exploring the use of zebrafish for personalized medicine. Due to the ease of observation, we are using pigmentation as a model.