{"doi":"10.1101/2024.02.02.578510","title":"Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells","abstract":"Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in 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, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment. By experimentally testing predictions based on TRN simulations, we show that drug treatment drives surviving PD-GSCs along a trajectory of intermediate states, exposing vulnerability to potentiated killing by siRNA or a second drug targeting treatment-induced transcriptional programs governing non-genetic cell plasticity. Our findings demonstrate an approach to uncover TRN topology and use it to rationally predict combinatorial treatments that disrupts acquired resistance in GBM.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":489982,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":680059,"name":"Parvinder Hothi","orcid":"0009-0003-0977-0562","position":1,"is_corresponding":false},{"id":441559,"name":"Adrián López García de Lomana","orcid":"0000-0002-9748-347X","position":2,"is_corresponding":false},{"id":441560,"name":"Min Pan","orcid":"0000-0002-9781-0637","position":3,"is_corresponding":false},{"id":1335289,"name":"R. Brent Calder","orcid":"0009-0008-1115-1046","position":4,"is_corresponding":false},{"id":441561,"name":"Serdar Turkarslan","orcid":"0000-0003-1679-6405","position":5,"is_corresponding":false},{"id":705124,"name":"Wei‐Ju Wu","orcid":"0000-0002-0022-2602","position":6,"is_corresponding":false},{"id":1335290,"name":"Hwahyung Lee","orcid":"0009-0003-2212-9462","position":7,"is_corresponding":false},{"id":28995,"name":"Anoop P. Patel","orcid":"0000-0001-7078-9535","position":8,"is_corresponding":false},{"id":278630,"name":"Charles Cobbs","orcid":"0000-0001-7688-4293","position":9,"is_corresponding":false},{"id":37887,"name":"Sui Huang","orcid":"0000-0002-3545-4665","position":10,"is_corresponding":false},{"id":400246,"name":"Nitin S. Baliga","orcid":"0000-0001-9157-5974","position":11,"is_corresponding":false},{"id":522257,"name":"James H. Park","orcid":"0000-0002-6551-2037","position":0,"is_corresponding":true}],"reference_count":147,"raw_metadata":null,"created_at":"2026-07-19T02:08:32.775003Z","pmid":"38370784","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}