Modeling of Protein Signaling Networks in Clinical Proteomics

Abstract

Molecular interactions that underlie pathophysiological states are being elucidated using techniques that profile proteomicendpoints in cellular systems. Within the field of cancer research, protein interaction networks play pivotal roles in the establishmentand maintenance of the hallmarks of malignancy, including cell division, invasion, and migration. Multiple complementarytools enable a multifaceted view of how signal protein pathway alterations contribute to pathophysiological states.One pivotal technique is signal pathway profiling of patient tissue specimens. This microanalysis technology provides a proteomicsnapshot at one point in time of cells directly procured from the native context of a tumor microenvironment. To studythe adaptive patterns of signal pathway events over time, before and after experimental therapy, it is necessary to obtain biopsiesfrom patients before, during, and after therapy. A complementary approach is the profiling of cultured cell lines with andwithout treatment. Cultured cell models provide the opportunity to study short-term signal changes occurring over minutesto hours. Through this type of system, the effects of particular pharmacological agents may be used to test the effects of signalpathway inhibition or activation on multiple endpoints within a pathway. The complexity of the data generated has necessitatedthe development of mathematical models for optimal interpretation of interrelated signaling pathways. In combination,clinical proteomic biopsy profiling, tissue culture proteomic profiling, and mathematical modeling synergisticallyenable a deeper understanding of how protein associations lead to disease states and present new insights into the design oftherapeutic regimens.