{"doi":"10.1073/pnas.2423894122","title":"Breast cancer cell coculture induces normal lung fibroblast transition to CAFs, promoting tumor cell dormancy and therapy resistance","abstract":"Cancer-associated fibroblasts (CAFs) shape the tumor microenvironment of primary breast tumors to promote tumor progression and therapy resistance. While the lung is a top metastatic site in breast cancer, the origins of lung metastasis-associated fibroblasts and their influence on disseminating tumor cell outgrowth and chemoresistance are poorly understood. Here, we demonstrate the applicability of 2-dimensional and 3-dimensional cocultures of primary human lung fibroblasts (LF) and breast cancer cells (BCC) as models of tumor-stromal interactions in lung metastatic breast cancer. Using these models, we find that BCC lines representing clinically relevant molecular subtypes differentially induce CAF-like phenotypes in primary LFs corresponding with their propensity for lung metastasis. Furthermore, we identify a mechanism by which juxtacrine signaling from LFs to triple negative breast cancer (TNBC) cells promotes expansion of prognostic dormant-like cell subpopulations and instigates autophagy-dependent therapy resistance via integrin and Janus kinase1/2 signaling. A high content kinase inhibitor compound library screen using this model identifies vacuolar protein sorting 34 as a therapeutic vulnerability unique to BCC-LF interaction whose inhibition can resensitize TNBC cells to chemotherapy and relieve LF-mediated extrinsic therapy resistance. Therefore, we propose coculture of primary human LFs and BCC as a reductionist model of interactions between tumor cells and lung-resident stroma and a tool for therapeutic and mechanistic discovery in lung metastatic breast cancer.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":548791,"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":0.9497,"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":652258,"name":"Kathryn E. Cronise","orcid":"0000-0003-3224-1469","position":1,"is_corresponding":false},{"id":643854,"name":"Eric P. Palmer","orcid":null,"position":2,"is_corresponding":false},{"id":1442967,"name":"Kelly McAuliffe","orcid":null,"position":3,"is_corresponding":false},{"id":1442968,"name":"Claire Stratton","orcid":null,"position":4,"is_corresponding":false},{"id":1442479,"name":"Kathryn E. Sparks","orcid":"0009-0003-4602-6775","position":5,"is_corresponding":false},{"id":1442969,"name":"Kendall Malmstrom","orcid":null,"position":6,"is_corresponding":false},{"id":1442970,"name":"Gwyneth Knott-Byars","orcid":null,"position":7,"is_corresponding":false},{"id":469869,"name":"Qiong Zhou","orcid":"0000-0002-8240-0440","position":8,"is_corresponding":false},{"id":491596,"name":"Hector Esquer","orcid":"0000-0002-1911-1523","position":9,"is_corresponding":false},{"id":469872,"name":"Daniel V. LaBarbera","orcid":"0000-0001-9460-3862","position":10,"is_corresponding":false},{"id":353888,"name":"Daniel P. Regan","orcid":"0000-0002-3148-1332","position":11,"is_corresponding":false},{"id":1442478,"name":"Marika L. Klosowski","orcid":"0000-0001-9548-9088","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T02:54:03.053965Z","pmid":"41269792","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":[]}