Abstract B34: Multigenic models of metastatic colon cancer in Drosophila

Abstract

Abstract Colon cancer is the third most common form of cancer and the second leading cause of cancer-related death in theWestern world. When it is detected at late stages with distant metastases already present, it is unlikely to be curable. This is largely due to the resistance of many late stage tumors to most targeted therapies and even chemotherapy. Development of new animal models of colon cancer that reflect the complex, multigenic and heterogeneous nature of human tumors will be essential in improving our ability to understand the biology of this disease and develop new targeted therapies. The Drosophila colon is remarkably similar to the human colon in terms of the signaling pathways that regulate its maintenance. We took advantage of this similarity to establish models of metastatic colon cancer in Drosophila that closely reflect features of human cancer. To this end, we utilized recent mutational profiling data from human colon tumors to generate flies carrying double, triple and quadruple combinations of mutations that are frequently found together in human tumors. We then investigated the tumorigenic and metastatic potential of these combinations by targeting them specifically to the adult Drosophila colon. We focused our initial analysis on three quadruple combinations: 1) rasG12V p53RNAi apcRNAi ptenRNAi, 2) rasG12V p53RNAi apcRNAi Smad4RNAi and 3) egfr p53RNAi apcRNAi Smad4RNAi. Colon epithelial cells carrying these combinations of mutations started expressing metastasis-related factors and established membrane processes; we are currently exploring the molecular nature of these tumor-like phenotypes. Eventually, these cells migrated through the basal membrane and the surrounding visceral muscle layer and colonized other sites within the body to form secondary tumors. Interestingly, these migratory cells were often found closely associated with trachea, a tubular network that provides oxygen to tissues in Drosophila. A more detailed characterization of the behavior of these cells as they leave the gut epithelium, as well as the secondary tumors are currently underway. We are also investigating emergent properties of these combinations by monitoring the behavior of cells carrying various double and triple combinations that make up the quadruple combinations we first analyzed. These models provide excellent paradigms to study tumorigenesis and metastasis in the context of a whole animal. Our findings will also shed light on the heterogeneity found in individual tumors, an important step towards personalized medicine. Citation Information: Cancer Res 2009;69(23 Suppl):B34.