{"doi":"10.1016/j.drup.2025.101321","title":"Disruption of NANOG-driven epithelial-mesenchymal transition (EMT) and self-renewal restores drug sensitivity in colorectal cancer","abstract":"<h4>Aims</h4>To investigate the regulatory role of NANOG in genes associated with stemness, symmetric division, and therapeutic resistance in colorectal cancer stem-like cells (CRC-SCs), with a focus on ERK/GSK-3β/β-catenin signalling and epithelial-mesenchymal transition (EMT), in order to evaluate the translational potential of targeting NANOG-associated signalling pathways.<h4>Methods</h4>Stemness, signalling activity, and cell division modes were analysed using 3D colonospheres enriched for CRC-SCs. Drug responses to the MEK inhibitor U0126 and the GSK-3β inhibitor TDZD-8 were assessed in CRC patient-derived organoids (PDOs), alongside molecular assays, immunohistochemistry with H-score quantification in xenograft models, and molecular dynamics simulations.<h4>Results</h4>NANOG overexpression enhanced the expression of stemness-associated genes, promoted symmetric cell division, and activated ERK/GSK-3β signalling, contributing to increased sphere formation. Inhibition of MEK and GSK-3β reduced EMT, cell proliferation, and symmetric division in CRC-SCs. NANOG-mediated dysregulation of ERK/GSK-3β altered β-catenin signalling and disrupted E-cadherin-dependent cell-cell adhesion. Molecular simulations and drug assays demonstrated that TDZD-8 and U0126 interfere with NANOG-DNA binding and β-catenin/E-cadherin interactions.<h4>Conclusions</h4>NANOG drives CRC-SC maintenance via ERK/GSK-3β/β-catenin signalling and EMT modulation. This study offers significant insights into the translational impact of targeting NANOG and its downstream pathways with small-molecule inhibitors U0126 and TDZD-8 and presents a promising strategy to reduce CRC-SCs stemness, functionality, and tumourigenicity.","journal":"Drug Resistance Updates","year":2026,"id":10671,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"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":0.0404,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2026-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":87988,"name":"Sameerah Shaheen","orcid":"0000-0003-0646-1847","position":1,"is_corresponding":false},{"id":87989,"name":"Miao Xue","orcid":"0000-0002-2040-6492","position":2,"is_corresponding":false},{"id":87990,"name":"Amirreza Mazloomi","orcid":null,"position":3,"is_corresponding":false},{"id":87991,"name":"Sepideh Youssefi","orcid":null,"position":4,"is_corresponding":false},{"id":87992,"name":"Hossein Kashfi","orcid":null,"position":5,"is_corresponding":false},{"id":87993,"name":"Mehreen Ahmed","orcid":"0000-0002-0422-2343","position":6,"is_corresponding":false},{"id":87994,"name":"Roya Babaei-Jadidi","orcid":null,"position":7,"is_corresponding":false},{"id":80135,"name":"Bradley Spencer‐Dene","orcid":"0000-0001-9533-5839","position":8,"is_corresponding":false},{"id":63290,"name":"Dominique Bonnet","orcid":"0000-0002-4735-5226","position":9,"is_corresponding":false},{"id":87995,"name":"Chris Denning","orcid":"0000-0003-0802-8617","position":10,"is_corresponding":false},{"id":87996,"name":"Abdolrahman S. Nateri","orcid":"0000-0002-6422-6813","position":11,"is_corresponding":false},{"id":87997,"name":"Roya Babaei‐Jadidi","orcid":"0009-0007-5001-3124","position":12,"is_corresponding":false},{"id":87987,"name":"Kiarash Saleki","orcid":"0000-0003-4159-7299","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"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":[]}