Xiphophorus Genetic Stock Center

Dr. Manfred Schartl

Co-PI for the XGSC

My main research interests are the molecular processes in organismic development and their malfunction in cancerogenesis. One major topic is signal transduction and gene regulation in melanoma. I use the Xiphophorus model system and transgenic medaka that develop different types of pigment cell tumors. Besides classical tools for biochemical characterization of signal transduction and transcriptional regulation, I use genome sequencing and RNA-Seq transcriptomics in a comparative approach of fish models with human data to identify new melanoma genes and small non-coding RNAs that are involved in the transition from a benign pigmentary lesion to malignant melanoma. For functional studies we have set up various cell culture systems from fish, mouse and human melanoma to measure the readouts of single malignant transformation parameters. This is complemented by studies with transgenic and CRISPR/Cas9 knockout fish. My team has pioneered the use of small aquarium fish models for cancer research. After isolating the first melanoma oncogene from a model organism our research has uncovered the importance of Ras/Raf/MAPK signaling for melanoma formation, which today is recognized to be responsible for more than 60% of human melanomas. Although my research is rooted in basic science to understand the genetic, molecular and cellular basis of cancer formation, I have always paid keen attention on the translational aspect of my results. I have set up assistant and associate professor teams at my chair that work on mouse models and human cancer cell lines and have frequently collaborated with clinical scientist. Comparative studies have resulted in the characterization of molecules and cellular processes first detected in fish models that show relevance for diagnostics and therapy of the human disease. At the Medical school of my university I have initiated the use of next generation sequencing in cancer patient diagnosis. I developed with my colleagues from Dermatology a targeted sequencing genetic diagnosis for melanoma patients, which is now adapted to new technological development. This program was so successful that other clinical units of the Comprehensive Cancer Center have quickly also adopted this methodology for their patients. In our NIH funded project together with my colleagues at Texas State University, I have developed a new screening system based on transcriptome changes in melanoma developing fish for detection of anti-cancer drugs from high-throughput testing of chemical libraries.

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Dr. Yuan Lu

Co-PI for the XGSC

Research Interests

My research focuses on using the Xiphophorus model system to identify an endogenous EGFR regulator utilizing transcriptomics and genome wide association studies. Bateson–Dobzhansky–Muller (BDM) model, a milestone theory explaining evolution and speciation, describes the negative epistatic interactions that occur between genes with a different evolutionary history to account for genetic incompatibility. Since early 1900’s when the BDM model was forwarded, such BDM incompatibility have been described in only a few non-vertebrate cases. Xiphophorus fish serve as the only vertebrate system that supports the BDM model, and showed tumorigenesis is a mechanism that accounts for post-zygotic isolation. Xiphophorus interspecies hybrid develop tumorigenesis due to genetic incompatibility between two loci, one is identified to be a mutant copy of egfr, while the other is left to be determined. The understanding of the regulatory mechanism on EGFR can progress our understanding on EGFR regulation in human disease and potentially lead to novel therapeutic approach that may overcome currently met resistance in EGFR inhibitors. We have forwarded a hypothetical tumor suppressor locus in Xiphophorus maculatus genome to a 110 Kbp region in chromosome 5 and have shown that Xiphophorus melanoma and human melanoma share similar gene expression pattern and may also rely on similar signaling pathways in disease progression. My research also includes the characterization of light-induced genetic response in several aquatic model systems, including Xiphophorus, medaka, zebrafish and using Xiphophorus interspecies hybrid, and allele specific gene expression to identify key genetic response to environmental cues such as light. My previous research experience includes characterization of ligand-independent and ligand-dependent transcription target of ERRβ in human prostate cancer cells, and screening botanical extract for prostate cancer therapy.

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Dr. Caitlin Gabor

Co-PI for the XGSC

Research Interests

My research program spans population level questions using conservation physiology and behavioral and evolutionary ecology with fish and amphibians as model organisms. My lab studies the historical forces of natural and sexual selection on speciation in a unisexual-bisexual species complex of live bearing fish from a population, behavioral, genetic and physiological standpoint. Currently, our work focuses on the consequences of anthropogenic stressors on live-bearing fish and amphibian declines using a holistic framework that evaluates mechanisms (e.g., genetic and physiology) through function (e.g., evolutionary and conservation implications). Specifically, we have been focusing on the consequences of land use conversion on multiple measures of physiological health, life history traits, and fitness of mosquitofish, Gambusia affinis, and multiple species of amphibians to explore evolutionary questions about population persistence in the face of change. We propose to extend our work to include cognition, community ecology, additional physiological measures, microbiome, and population genetic question with collaborators. As multi-PI for the Xiphophorus Genetic Stock Center I will help maintain the current successful research and I propose to bridge my research program with the current research programs. I see important links between life-history evolution, cognition and behavior, stress physiology, gene expression, microbiome, ecotoxicology and broad population genetic and evolutionary questions. I think taking a population level perspective using model fish at the Xiphophorus Genetic Stock Center will help expand our understanding of how anthropogenic change affects organismal fitness, such as via affecting rates of cancers, changes in cognitive function, stress levels, reproduction and behavior. These studies could also aid in understanding human responses to change.

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