Description of Research Expertise

The primary research focus of my laboratory is using systems biology to understand human tumor evolution. Specifically, I am interested in understanding how properties of cellular networks influence the specific sequence of mutations that can give rise to a tumor in a given cell type. Our primary approach utilizes bottom-up, high-resolution mass spectrometry in conjunction with protein microarrays to measure specific changes in the proteome and phospho-proteome characterizing cells at various points along the transformation pathway.

We are currently utilizing neuroblastoma as a model system. Neuroblastoma accounts for ~15% of childhood deaths due to cancer, and as such it is of substantial clinical significance. Additionally, neuroblastoma has several characteristic subtypes that appear to reflect alternative evolutionary pathways. For these reasons, it is an ideal model system in which to investigate the ways that cellular network properties influence and are influenced by specific genomic alterations. As an adjunct to these studies, we are analyzing changes in yeast protein-protein interactions resulting from telomere disruption in order to better understand the ways in which these types of data may contribute to our understanding of mammalian tumor behavior and aging.

A critical component of these investigations will be the ability to not only classify tumors on the basis of a proteomic and/or phospho-proteomic patterns but also to understand the combinations of changes in intracellular pathways that give rise to these patterns. We are currently designing studies that will allow us to create a library of proteomic patterns arising from defined cellular perturbations. We hypothesize that this library, in combination with an extension of bioinformatics techniques that we have previously used to interpret patterns in complex cellular mixtures, will allow us to detect disruption of a large set of known cellular pathways using MS-based proteomic profiling.

In addition to its use as a basic research tool for studying pathways of tumor evolution, such a library would also be of substantial clinical utility. Specifically, it would enable diagnostic interpretation of tumor specimens at the level of functional cellular subnetworks, thereby providing the necessary diagnostic platform on which a “personalized medicine” therapeutic approach can be based. Given the substantial potential of these approaches for clinical laboratory medicine, my laboratory is strongly interested in using this combination of proteomic profiling with novel bioinformatics analyses for both biomarker discovery and diagnostic translation in a number of disease states.