The Bennett Family Distinguished Lecture Series 2014

Dr. Joe Gray

Spatial Systems Biology of Cancer

Dr. Joe W. Gray, a physicist and an engineer by training, holds positions as the Gordon Moore Endowed Chair, Biomedical Engineering Department Chair; Director, Center for Spatial Systems Biomedicine; and Associate Director for Translational Research, Knight Cancer Institute at the Oregon Health & Science University. He is also Emeritus Professor, University of California San Francisco; and Senior Scientist, Lawrence Berkeley National Laboratory. He was Professor of Laboratory Medicine at the University of California, San Francisco (1991-2011), and Associate Laboratory Director for Biosciences and Life Sciences Division Director at the Lawrence Berkeley National Laboratory (2003-2011). He is Principal Investigator of the National Cancer Institute / Integrative Cancer Biology Program (ICBP) Center for Cancer Systems Biology (CCSB) aimed at understanding and modeling of RTK signaling, PI of a DOD Innovator project aimed at improving early breast cancer detection, Co-investigator on human and mouse cancer genome atlas projects, and PI of a Keck Project to initiate development of image-based approaches that will allow architectural analyst of the nanoscale molecular assemblies that regulate information flow in cells.

Abstract:

International efforts have now defined the genomic landscapes of most major human cancer types. The genomic landscape of breast cancer is particularly well described in several recent publications. The high level view of this disease suggests a remarkable level of inter- and intra-tumor heterogeneity, the presence of a few recurrent and many rare genomic aberrations and substantial genomic and epigenomic heterogeneity. The challenge now is to understand how these aberrations and tumor extrinsic influences from the microenvironment collaborate to deregulate aspects of cell differentiation, proliferation, apoptosis, DNA repair, senescence, motility and multiscale architecture that include cancer progression and response to therapy. To this end, the OHSU Center for Spatial Systems Biomedicine has deployed a suite of measurement technologies that enable high throughput assessment of changes in these endpoints to siRNA knockdown of genes found by the TCGA and international genomics efforts to be aberrant and/or involved in regulatory networks that are associated with differentiation subtype and/or differential response to therapy. These studies have revealed both recurrent and rare aberrations that strongly influence these endpoints as well as a range of molecular architectures that influence aspects of receptor tyrosine kinase signal transduction. This presentation will summarize the results of the siRNA knockdown experiments and focus on the concept that analysis of the architectural features influenced by genomic and epigenomic abnormalities will suggest new therapeutic approaches. Illustrative examples of architectural features revealed using advanced imaging approaches that suggest new approaches to the design of RTK targeted therapies include (a) Ras/Raf multimers associated with signal transduction, (b) actin associated microfilaments involved in ERBB2 signal transduction, and (c) intratumor heterogeneity in differentiation status that influences responses to a range of kinase inhibitors.