Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering (ENAS)

First Advisor

Levchenko, Andre

Abstract

Cell plasticity enables cancer cells to transition between distinct phenotypic states, driving heterogeneity and therapeutic resistance. Here, I present the RACE (Rapid Analysis of Cell phenotypic Extremes) assay, a longitudinal in vitro experimental model designed to functionally isolate and enrich fast- and slow-migrating glioblastoma (GBM) cell subpopulations in response to mechanical input imposed by an extracellular matrix (ECM)-mimicking nanofabricated platform with pro-migratory property. I tracked these phenotypically distinct subpopulations and characterized their dynamic evolution through bulk and single-cell transcriptomic profiling. I found that fast- and slow-migrating cells corresponded to mesenchymal- and proneural-like transcriptional programs, respectively, and were regulated by a mutually inhibitory mechanism between MYC-mediated proliferation and TP53/JNK-mediated stress response signaling. Through the unique perspective of the landscape model, we showed that plasticity property could be modulated, for example by ECM stiffness, and by reshaping the "barrier" between cell state "attractors". Notably, we discovered that high plasticity property or lowering the "barrier" was marked by gene signatures of elevated protein synthesis/degradation, enhanced stress response, and suppressed cell proliferation. Together, this work provided both a conceptual framework and an experimental toolkit for measuring and dissecting functional plasticity in GBM.

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