Genetic of cancer and tumor angiogenesis in zebrafish

Research project

Overview

Our research focuses on using the zebrafish to better understand human cancer and develop models that provide insights into the mechanisms of transformation by oncogenes. The zebrafish offers a number of features, such as its rapid development, tractable genetics, suitability for in vivo imaging and chemical screening that make it a useful model to cancer researchers. The use of zebrafish models allows the study of cancer cell biology, large-scale genetic and epigenetic events in cancer and the development of therapies to be addressed in an integrated way.
( link to: http://dmm.biologists.org/content/early/2010/03/25/dmm.004747.long ).

Project 1 - Mechanisms of oncogenic transformation

We have established a set of zebrafish models to study a powerful oncogene, HRAS, in the context of a vertebrate organism and with different spatial and temporal degrees of expression. In the first model, germline integration of a GFP:HRASV12 transgene leads to constitutive expression of a traceable (fluorescent) oncogene and results in a number of developmental abnormalities that recapitulate the clinical features of Costello syndrome (link to http://dmm.biologists.org/content/2/1-2/56.long). In this zebrafish model of Costello syndrome, some defects are caused by an oncogene-induced senescence program in adult proliferating cells. This finding encourages further investigation of cellular senescence in Costello patients, who show an age-dependent worsening phenotype that is compatible with premature exhaustion of adult progenitor cells. Additionally, understanding how a developing organism restricts oncogenic signal activation might lead to novel therapeutic strategies in cancer.
In a second model, expression of GFP:HRASV12 is regulated by the binary Gal4/UAS system for controlled expression of the oncogene in specific cells. Crossing of the oncogenic UAS:GFP-HRASV12 line with different Gal4 drivers generates specific cancer types in different organs. One of these models is a highly penetrant, progressive form of melanoma, which we are using to address the role of epigenetic modifications in cancer progression (link to http://www.liebertonline.com/doi/abs/10.1089/zeb.2009.0612).

Project 2 - Tumor angiogenesis

Blood and lymphatic vessels are a necessary component of solid tumors, providing oxygen and metabolites needed for growth and a preferential route for metastatic dissemination. We use transgenic zebrafish lines to ease the analysis of the vascular phenotypes induced by perturbing gene function, as well as molecular, genetic and embryological manipulations to uncover the genetic pathways involved in normal and tumoral angiogenesis
(links to: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0005772
http://www.sciencemag.org/cgi/content/full/324/5935/1710
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827862/?tool=pubmed ).