Abstract 3180: In vitro tool for discovering oncogenes and tumor suppressor genes in a system's manner.

Abstract

Abstract The molecular complexity of cancer still remains as the limiting factor for developing efficient therapies with minimal side effects. However, scientists succeeded in determining common alterations in most human cancer types. Each of these alterations results from disruption of an anti-cancer regulation mechanism and/or activation of cancer-promoting networks by genetic and epigenetic changes. As a consequence, cancer cells become capable of mimicking stem cells’ ability to proliferate indefinitely while maintaining their cellular identity, or to self-renew, which is crucial for any type of stem cell. Indeed, some of the networks which are deregulated in cancer normally regulate self-renewal in stem cells. However, self-renewal is tightly regulated in stem cells, while cancer cells manage to escape the internal and external regulation mechanisms. Hence, cancer cells differ from stem cells by displaying disruptions in feedback mechanism controlling the rate of cell division, aberrant differentiation programs and error-prone replication, so they become invasive and even metastatic. We hypothesize that the stemness regulatory “cassette” that serves limitless replicative potential and undifferentiated state is a measure of cancer virulence and progression. We believe that this gene cassette is established through different mechanisms in each cell type, so it can be separated from invasion and instability in a precise and defined manner. To test our hypotheses, we set up a system reconstruction model consisting of induced pluripotent cells and transformed cells as stem and cancer cell models respectively, and their source of primary mouse embryonic fibroblast cells. From this model system, we created a system's map for transformation using differential expression patterns from whole genome expression arrays. We discovered gene networks that are common between stem and cancer cells, but different from their primary cells of origin. We also found deregulated/activated cassettes which are unique for cancer cells and which are hardwired by genomic rearrangements (copy number and structural variations) identified by DNA paired end tag (DNA-PET) sequencing and single nucleotide variations using RNA sequencing. We are now investigating the role of candidate genes selected from this analysis in cancer and stem cell maintenance through a high content siRNA screening. Citation Format: Gaye Saginc, Leena Ukil, Xingyi Woo, Francesca Menghi, Denis Bertrand, Charlie Wah Heng Lee, Koichiro Inaki, Edison Tak Bun Liu. In vitro tool for discovering oncogenes and tumor suppressor genes in a system's manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3180. doi:10.1158/1538-7445.AM2013-3180