A synthetic systems biology approach to predict context-specific mechanisms for SHP2 functional activity and resistance to SHP2 inhibition

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PROJECT SUMMARY/ABSTRACT Oncogene activation is modulated by normal subcellular compartments that execute specialized functions related to hallmark cancer phenotypes. These organelles must adapt to oncogenic stress in order for tumors to initiate and progress, but there is little to no systems-level understanding of how such adaptations occur and what vulnerabilities might be created. The Systems Analysis of Stress-adapted Cancer Organelles (SASCO) Center at the University of Virginia will address this challenge by mechanistic modeling of organellar processes that iterates with quantitative experiments in disease-relevant cell cultures and primary tumors. The working SASCO Center hypothesis is that organelle-specific adaptation to oncogenic stress occurs through a few critical bottlenecks, which become identifiable once the relevant signaling, metabolic, and transport pathways have been properly integrated. The Center brings together 14 investigators with primary and collaborative track records in cancer biology, systems biology, genetically engineered mouse models of cancer, and clinical practice. Three Research Projects and one Shared Research Core will pursue a common research strategy, which leverages mechanistic models to test competing alternative hypotheses about how organelles adapt to stresses from proximal oncogenes that drive specific types of cancer. The Projects are organized hierarchically as organelle stresses downstream of proliferation-inducing oncogenes. Project 1 will examine the chromosome passenger complex and its regulated phase separation during metaphase as an organelle that senses and repairs spindle defects to suppress breast cancer aneuploidy driven by mitotic transcription factors. Project 2 will evaluate the metabolic consequences of chronic mitochondrial fragmentation caused by mutant KRAS in primary colorectal cancers and secondary liver metastases. Project 3 will investigate localized signal-transduction rebalancing as a mechanism for alleviating plasma-membrane stress caused by EGFR amplification in glioblastoma. All Research Projects will rely on the High-Content Imaging & Analysis Core to obtain iterative multichannel immunofluorescence data with organelle-level resolution and quantification. The SASCO Outreach Core amplifies ongoing programs at the University of Virginia to provide summer research experiences for undergraduates and faculty scholars from historically underrepresented backgrounds as well as introductory systems biology modeling materials for clinicians across the Commonwealth of Virginia. The SASCO Center will thus create a national headquarters for subcellular cancer systems biology within the broader Cancer Systems Biology Consortium.