Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells

• DOI: 10.1101/2024.02.02.578510
• Publication Date: 2024-02-08T01:40:32Z
• Authors: James H. Park; Parvinder Hothi; Adrian Lopez Garc...; Min Pan; Rachel Calder; Serdar Turkarslan; Wei-Ju Wu; Hwahyung Lee; Anoop P. Patel; Charles Cobbs; Sui Huang; Nitin S. Baliga
• Keywords: Temozolomide; Gene regulatory network

ABSTRACT Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity treatment-induced shifts phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, drives recurrence. Through inference transcriptional regulatory networks (TRNs) patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology transcription factor interaction distinct trajectories state transitions PD-GSCs resistant or susceptible cytotoxic treatment. By experimentally testing predictions based on TRN simulations, show that treatment surviving along a trajectory intermediate states, exposing vulnerability potentiated killing by siRNA second targeting programs governing non-genetic plasticity. Our findings an approach uncover use it rationally predict combinatorial treatments disrupts acquired GBM. Teaser Gene drive response drug-induced cell-state leading resistance.