Analysis of the regulatory networks regulating district stem cell-like states in aggressive cancers

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Project Summary/Abstract The work proposed here is an extension of the work performed by the Yale Cancer Systems Biology Center over the last 5 years. It is an extension of the work stemming from but not proposed in the initial application. The project detailed in this application will focus on the use of multi-OMIC approaches to reconstruct the regularity networks driving phenotypic plasticity in cancer cells, and more specifically cancer stem cells. Although this was not initially anticipated, we discovered that glioblastoma cell line and possibly glioblastoma patient samples harbor stem cell populations that differ in their properties, particularly with respond to activation of signaling pathways and activation of Rho-family small GTPases, Rac1 (Rac) and RhoA. The multi- OMIC (transcriptomic, proteomic and phosphorus-proteomic) analysis cells displaying greater invasive motility behavior in the context of bio-mimetic and clinically relevant RACE assay used in the work of the Center, appear to primarily activate RhoA, through a variety of mechanisms relying on activation of AKT-mTOR and RelB NF-kappaB signaling. On the other hand, cell displaying lower motility under these conditions appear to activate stress response pathways, particularly JNK and p38 and a distinct small GTPase, Rac, antagonistic to RhoA. This picture will be supplemented over the course of the project with additional experimental and data analysis work, extending the analysis to characterization of epigenetic signatures of each of the phenotypic states. We will also explore whether the cell motility behavior may be altered in distinct micro-environments, favoring Rac-dependent rather RhoA-dependent motility. Furthermore, we hypothesize that both phenotypic states may promote invasive spread, but through distinct routes within the brain tissue, e.g., through peri- vascular spaces vs. through fibrous environment of corpus callosum or other fibrous areas of the brain. We will test this hypothesis in various engineered and tissue models of cellular micro-environments. We anticipate that the analysis undertaken during this cost extension project will substantially improve our understanding of the phenotypic plasticity in brain and other cancers and will pave the way to more intelligent treatments mitigating cancer growth and invasive spread.