Genomic and epigenetic changes occurring during carcinogenesis: A fly perspective. Delphine Fagegaltier¹, Mary-Lee Dequeant², Gregory Hannon¹, Norbert Perrimon², Amanda Simcox³, STARR Consortium. 1) CSHL - HHMI, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; 2) HHMI - Department of Genetics Harvard Medical School Boston, MA; 3) Department of Molecular Genetics Ohio State University Biological Sciences Columbus, OH.

   Despite tremendous efforts in various organisms, the questions of how cancer cells initially become transformed, which pathways are involved in reaching a transformed state, and whether each cell takes the same route to reach such a state remain poorly understood. To answer these questions we are using the Drosophila model to study the basic mechanisms by which genomes coordinate their genetic and epigenetic responses towards a transformed state activated by specific oncogenes or tumor-suppressors. This STARR consortium project has three major aims : i) generating Drosophila cell lines with cancer-relevant genotypes; ii) profiling the transcriptional and epigenetic changes that occur during the establishment of these cell lines; iii) addressing whether cells remain addicted to the presence of the initiating oncogene or loss of tumor suppressor and establish which factors are required for the cells to proliferate and maintain a transformed state. We have established various cell lines expressing an oncogene or depleted for a tumor-suppressor. A pilot array experiment on primary cell lines derived from ras oncogene expressing embryos suggests that cells undergo major epigenetic changes via the Polycomb Group of proteins before reaching a transformed state. To further confirm the role of these proteins during transformation, we have compared the transcriptomes of a larger set of transformed cell lines using RNA-Seq. By dissecting the progressive transcriptional changes generated during transformation, these studies shed light to general mechanisms and pathways leading to tumorigenesis and reveal changes specific of each oncogenic molecule studied.