Abstract 1109:In vivoloss of function screening reveals carbonic anhydrase IX (CAIX) as a key modulator of tumor initiating potential in primary pancreatic tumors

Re-programming of energy metabolism is one of the emerging hallmarks of cancer. Upregulation of energy metabolism pathways fuels cell growth and division, a key characteristic of neoplastic disease, and can lead to dependency on specific metabolic pathways. Thus targeting energy metabolism pathways might offer the opportunity for novel therapeutics. Here we describe the application of a novel in vivo screening approach for the identification of genes involved in cancer metabolism using a patient derived pancreatic xenograft model. Lenti-viruses expressing shRNAs targeting twelve different cell surface protein transporters were separately transduced into the primary pancreatic tumor cells. Transduced cells were pooled and implanted into mice. Tumors were harvested at different times and the frequency of each shRNA was determined as a measure of which ones prevented tumor growth. Several targets including CAIX, MCT4, and xCT were identified in these studies and shown to be required for tumor initiation and growth. Interestingly, CAIX was overexpressed in the tumor initiating cell population. CAIX expression alone correlated with a highly tumorigenic subpopulation of cells. Furthermore, CAIX expression was essential for tumor initiation since shRNA knockdown eliminated the ability of cells to grow in vivo. To the best of our knowledge, this is the first parallel in vivo assessment of multiple novel oncology target genes using a patient derived pancreatic tumor model.