Deciphering The Phenotypic Switch of Glioblastoma Cells

Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular Biophysics and Biochemistry

First Advisor

Levchenko, Andre

Abstract

Glioblastoma (GBM) is the most common and deadliest form of brain cancer. The high mortality rate is largely due to the invasive local spread of cancer cells into the surrounding tissue. Thus, it is important to understand the changes in the regulatory networks driving a shift from cell proliferation to invasive migration. To date, the information on the "go-or-grow" phenotypic plasticity in GBM has relied mostly on transcriptomic profiling of cells in the tumor bulk and periphery and the implication of some genes in controlling the invasive behavior. On the other hand, the post-translational modifications that may define the signaling networks regulating this phenotypic switch response remain relatively poorly characterized. Here, we use a previously characterized experimental platform mimicking invasive cells spread (which is predictive of clinical outcomes when used with primary patient-derived cells) coupled with a multi-omics analysis to identify and characterize phenotypically distinct GBM cell sub-populations. In particular, we focus on the phospho-proteomic analysis of more migratory and more proliferative phenotypic states isolated by the phenotypic filtering enabled by this platform. We extensively characterized the long-term dynamics of cell response to the extracellular matrix (ECM) cue triggering invasive cell spread within this experimental analysis, finding that the cell migratory state is enabled by the activation of a set of signaling networks, distinct and likely inhibitory of the pro-proliferative signaling. These networks mediate the response to cellular stresses, G2M checkpoint activation, an increase in mTOR signaling, and glycolytic metabolism. We further demonstrate that the phosphoproteomic signature can be highly predictive of disease-free survival of GBM patients.

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