GENOMICS OF APOPTOSIS & ANGIOGENESIS IN ISLET CARCINOMA

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Transgenic mouse models of cancer present a spectrum of experimental opportunities, including elucidation of pathways of tumor development and progression. As in human cancers, genetic changes during mouse tumorigenesis have the potential to be instructive about mechanisms underlying pathways to cancer. Over the last decade the RIP-Tag mouse model of islet cell carcinoma has proved a valuable prototype for investigating parameters of multistage tumorigenesis. Specific changes include characteristic losses of heterozygosity/DNA copy number on chromosomes 9 (designated LOH9) and 16 (LOH16), acquisition of resistance to apoptosis, and induction of angiogenesis. These observations have lead to the hypothesis that LOH9 encodes an apoptosis regulatory gene and LOH16 encodes an angiogenesis suppressor gene. This project brings together complementary talents of the Hanahan lab, which has expertise and experience in transgenic mouse models and their characterization, and the Gray lab, which has expertise in cancer genetics and in technologies for characterizing cancer cell genomes. Together these labs shall precisely determine the minimal extents of LOH9 and LOH16, test the hypothesis that apoptosis and angiogenesis are partly controlled by tumor suppressor genes in these regions and identify the involved genes, designated loh9 and loh16; respectively. In so doing, this project will shed light on the mechanism of tumorigenesis in this model, and serve to develop and refine technological strategies that should prove broadly applicable to mouse models of cancer. Specifically, this project will: Develop genome screening technologies to detect and fine structure map these tumor suppressor loci utilizing multiplex LOH and array-based CGH, and rigorously compare these techniques during the analysis of a bank of approximately 450 islet carcinomas; Assess the hypotheses that LOH9 encodes an apoptosis regulatory gene and that LOH16 encodes a gene that suppresses angiogenesis, using in vitro and in vivo bioassays in conjunction with genomic analysis, functional selection, and genetic complementation via BAC DNA transfer; Isolate loh9 and loh16 using functional complementation and/or positional cloning techniques, and begin to analyze their expression and roles in the islet carcinoma pathway, and in human cancers.