{"doi":"10.1101/2022.03.01.482539","title":"Loss of LGR5 through plasticity or gene ablation is associated with therapy resistance and enhanced MET-STAT3 signaling in colorectal cancer cells","abstract":"Abstract Plasticity plays a significant role in colorectal tumor initiation, progression, and drug resistance. LGR5 is highly expressed in colorectal cancer (CRC) and marks functional cancer stem cells (CSCs). While LGR5 + CSCs are tumor-initiating, the majority of CRC cells that disseminate to seed metastases are LGR5 - ; however, reemergence of LGR5 + CSCs is required to drive metastatic outgrowth. LGR5 + CSCs have been shown to convert to LGR5 - CRC cells in response to chemotherapies and this loss of LGR5 promotes a more drug-resistant phenotype. However, the molecular mechanisms that mediate plasticity remain elusive. In this study, we demonstrate conversion of LGR5 + CRC cells to an LGR5 - state in response to chemotherapy, LGR5-targeted antibody-drug conjugates (ADCs), or LGR5 gene ablation, led to activation of STAT3. Further investigation revealed increased STAT3 activation occurred a result of increased MET activity. LGR5 overexpression decreased MET-STAT3 activity and sensitized CRC cells to therapy. STAT3 inhibition suppressed MET phosphorylation, while constitutively active STAT3 reduced LGR5 levels and increased MET activity, suggesting a potential feedback mechanism. Combination treatment of MET-STAT3 inhibitors with irinotecan or ADCs substantiated synergistic effects in vitro. In CRC xenografts, STAT3 inhibition combined with irinotecan enhanced tumor growth suppression and prolonged survival. These findings suggest a mechanism by which drug-resistant LGR5 - CRC cells acquire a survival advantage through activation of MET-STAT3 and provide rationale for new treatment strategies that target CRC cell plasticity. Significance This study reveals that transition of highly plastic LGR5 + CRC cells to a more drug-resistant LGR5 - state involves activation of MET-STAT3 signaling and provides new insight into therapeutic strategies to combat plasticity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":301033,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":491803,"name":"Joan Jacob","orcid":"0000-0002-9756-8449","position":1,"is_corresponding":false},{"id":991906,"name":"Ashlyn Parkhurst","orcid":"0000-0002-1904-579X","position":2,"is_corresponding":false},{"id":985415,"name":"Shraddha Subramanian","orcid":"0000-0002-7351-5924","position":3,"is_corresponding":false},{"id":503164,"name":"Liezl E. Francisco","orcid":"0000-0002-3680-3767","position":4,"is_corresponding":false},{"id":701949,"name":"Zhengdong Liang","orcid":"0000-0003-4861-3941","position":5,"is_corresponding":false},{"id":330789,"name":"Kendra S. Carmon","orcid":"0000-0002-3244-6096","position":6,"is_corresponding":false},{"id":570123,"name":"Tressie A. Posey","orcid":"0000-0002-8141-4760","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T00:31:57.812980Z","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":[]}