My research team studies how perturbation of specific signal transduction pathways contributes to the initiation, progression and dissemination of cancer.  We employ a “systems level” integrative discovery platform to characterize pathway dynamics in normal and cancer cell models.  More specifically, we use mass spectrometry-based proteomics to define the protein-protein interaction networks for signaling pathways of interest (WNT, NRF2/oxidative stress).  We then annotate the nodes within the network for function, as determined by established and novel functional genomic screening technologies. Integration of these data with cancer-associated mutation data and cancer-associated gene expression data yields a powerful tool for oncological discovery—a cancer annotated physical/functional map for a specific signaling pathway of interest.  Critical to our success is the development and implementation of computational scoring algorithms, relational database construction and data visualization. Ultimately, the models and hypotheses produced are challenged through mechanistic studies employing cultured cancer cells, zebrafish, mice and in vitro biochemical systems.

In my presentation, I will give an overview of our recent work tackling two challenges facing the mass spectrometry-based proteomics. First, classifying false discoveries from large-scale protein-protein interaction networks is a quickly evolving arena within computational proteomics. We have contributed to this effort through the development of Spotlite. Second, although over 100,000 peptide species can be detected in a single mass spectrometry experiment, more than 80% of them will not be selected for sequencing. We are working on predictive real-time sequencing algorithms to increase protein sequencing depth.  I will also discuss two stories that began with protein mass spectrometry and have now progressed to new understanding of signal transduction in cancer. One of these discoveries is now supporting new preclinical trials in a particularly devastating subtype of B-cell lymphoma.