{"doi":"10.1101/2025.10.30.681251","title":"Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction","abstract":"Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes. In breast cancer, increased tumor stiffness is associated with elevated metastasis risk and poor survival. We identify a unique role of the JAK family kinase TYK2 in suppressing breast cancer metastasis under low ECM stiffness. Genetic or pharmacological inhibition of TYK2 in mammary acini and patient-derived organoids leads to invasion at low ECM stiffness by promoting Epithelial-Mesenchymal Transition, which is independent of cytokine-induced JAK/STAT signaling. TYK2 blockade promotes metastasis in breast tumor cell- and patient-derived xenografts. TYK2 localizes at the plasma membrane via IFNAR1 association under low stiffness, but it becomes cytoplasmic and inactivated at high stiffness. Normal human breast epithelium displays membrane-localized TYK2, whereas invasive breast tumors exhibit cytoplasmic TYK2. These findings uncover a TYK2-dependent mechanism by which ECM rigidity suppresses breast cancer metastasis and underscore the need for vigilant breast cancer screening in patients receiving TYK2 inhibitors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":579629,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"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":1490568,"name":"Hannah E. Majeski","orcid":null,"position":1,"is_corresponding":false},{"id":1301803,"name":"Aida Mestre‐Farrera","orcid":"0000-0003-1371-8487","position":2,"is_corresponding":false},{"id":1490182,"name":"Shirong Cai","orcid":"0009-0008-6101-6504","position":3,"is_corresponding":false},{"id":1490569,"name":"Arya Lalezarzadeh","orcid":null,"position":4,"is_corresponding":false},{"id":227576,"name":"Yichi Zhang","orcid":"0000-0003-3932-3088","position":5,"is_corresponding":false},{"id":312931,"name":"Kei‐ichiro Arimoto","orcid":null,"position":6,"is_corresponding":false},{"id":311115,"name":"Dong‐Er Zhang","orcid":"0000-0003-2541-6443","position":7,"is_corresponding":false},{"id":62849,"name":"Helen Piwnica‐Worms","orcid":"0000-0003-4210-6738","position":8,"is_corresponding":false},{"id":381774,"name":"Laurent Fattet","orcid":"0000-0001-5152-4937","position":9,"is_corresponding":false},{"id":1471483,"name":"Jing Yang","orcid":"0000-0002-9773-8065","position":10,"is_corresponding":false},{"id":1301804,"name":"Zhimin Hu","orcid":"0000-0002-9360-1686","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T02:58:34.718602Z","pmid":"41279022","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":[]}