{"doi":"10.1101/2025.08.22.671773","title":"L1CAM signaling through planar cell polarity generates SOX2 <sup>+</sup> metastatic progenitors in lung adenocarcinoma","abstract":"ABSTRACT Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unknown. Here, we elucidate a process that drives the emergence of SOX2 + metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells in the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions. L1CAM-mediated adhesion to perivascular basement membrane is known to stimulate the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive SOX2 expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2 + LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558864,"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":0.9456,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":243522,"name":"Yasemin Kaygusuz","orcid":null,"position":1,"is_corresponding":false},{"id":778475,"name":"Carson Kenum","orcid":"0009-0006-6597-2654","position":2,"is_corresponding":false},{"id":240160,"name":"Lan He","orcid":"0000-0003-4955-0380","position":3,"is_corresponding":false},{"id":1415965,"name":"Mohamed I. Gatie","orcid":"0000-0001-8500-5609","position":4,"is_corresponding":false},{"id":1024600,"name":"Xueqian Zhuang","orcid":"0000-0001-7012-3223","position":5,"is_corresponding":false},{"id":240161,"name":"Roshan Sharma","orcid":"0000-0001-9886-009X","position":6,"is_corresponding":false},{"id":1159879,"name":"Ronan Chaligné","orcid":"0000-0001-5788-5848","position":7,"is_corresponding":false},{"id":238379,"name":"Umesh Bhanot","orcid":"0000-0001-6656-1239","position":8,"is_corresponding":false},{"id":240165,"name":"Richard P. Koche","orcid":"0000-0002-6820-5083","position":9,"is_corresponding":false},{"id":14824,"name":"Tuomas Tammela","orcid":"0000-0003-3675-6961","position":10,"is_corresponding":false},{"id":255184,"name":"Anna‐Katerina Hadjantonakis","orcid":"0000-0002-7580-5124","position":11,"is_corresponding":false},{"id":1555,"name":"Charles M. Rudin","orcid":"0000-0001-5204-3465","position":12,"is_corresponding":false},{"id":54176,"name":"Joan Massagué","orcid":"0000-0001-9324-8408","position":13,"is_corresponding":false},{"id":1203186,"name":"Jin Suk Park","orcid":"0000-0002-8011-1995","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40894609","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":[]}