Abstract IA06: Spatial systems biology of cancer

Abstract

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. Citation Format: Joe Gray. Spatial systems biology of cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA06.