Abstract 4933: Novel insight into hallmark switch in cancer metabolism using the Interrogative Biology™ discovery platform

Abstract

Abstract Cancer metabolism is an intergrative ensemble of disrupted enzyme kinetics and dysregulated metabolite utilization leading to loss of normal cellular function that is the result of a multi-factorial yet coordinated breakdown in vascular, immune, cell cycle, apoptotic, and ECM components. In actively metabolizing cancer, the switch from mitochondrial OXPHOS to anaerobic glycolysis is very well characterized and understood. Global cellular changes in response to metabolic switch have either been overlooked or not been primary interest or relevance to cancer metabolism. We describe a novel systems biology/engineering approach encompassing cell models that are conditioned under various oncogenic perturbations or environments and then coupled with functional bioenergetic read out such as employing the XF24 Seahorse Bioscience analyzer, ATP assays, and ROS production. The OCR and ECAR measurements generated by XF24 analyzer enabled quantifying the switch from aerobic to the anerobic mode of energy metabolism. Cellular profiles were captured in the form of multi-omic (proteomic, genomic, proteomic) signatures using high-throughput mass spectrometry based protocols. Analyses were performed on oncogenic breast, prostate, liver, pancreatic, skin (melanoma, squamous cell carcinoma) and were compared to normal fibroblasts, keratinocytes, hepatocytes, kidney cells, adipocytes, and human aortic and endothelial cells. High throughput data cascades from various cancer states were integrated with the metabolic data from the XF24 analyzer using an AI-based data mining platform to generate causal network based on bayesian models (REFS™ model). The output enables the understanding of differential mechanisms that drive glycolysis and mitochondrial OXPHOS in a cancer versus normal environment. Further validation of prominent hub of activity as they partake as key drivers of metabolic end points by siRNA knockdown experiments followed by measurement using the XF24 analyzer confirmed the relevance of these hubs in cancer metabolism and their relevance as potential therapeutic targets and biomarkers for diagnostics development. The data output presented herein strongly suggest that the Interrogative Biology® platform is a key tool in deciphering differential network analysis pertinent to disease pathophysiology and bioenergetics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4933. doi:1538-7445.AM2012-4933