{"doi":"10.3390/cancers15061908","title":"Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells","abstract":"BACKGROUND: CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. METHODS: We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. RESULTS: Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-β- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-β-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. CONCLUSIONS: These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.","journal":"Cancers","year":2023,"id":335199,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9636,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":724189,"name":"Ghada M. Sharif","orcid":"0000-0001-5344-3575","position":1,"is_corresponding":false},{"id":568554,"name":"Marcel O. Schmidt","orcid":"0000-0002-3991-2766","position":2,"is_corresponding":false},{"id":1065137,"name":"B. R. Friedland","orcid":null,"position":3,"is_corresponding":false},{"id":1064561,"name":"Rohith Battina","orcid":"0009-0008-7331-7072","position":4,"is_corresponding":false},{"id":394720,"name":"Raneen Rahhal","orcid":"0000-0002-6428-1118","position":5,"is_corresponding":false},{"id":295094,"name":"John W. Davis","orcid":"0000-0003-3491-7194","position":6,"is_corresponding":false},{"id":449856,"name":"Irfan Khan","orcid":"0000-0003-3854-5420","position":7,"is_corresponding":false},{"id":288143,"name":"Anton Wellstein","orcid":"0000-0002-0570-4950","position":8,"is_corresponding":false},{"id":394721,"name":"Anna T. Riegel","orcid":"0000-0001-6585-8612","position":9,"is_corresponding":false},{"id":1064560,"name":"Gregory T. Gallanis","orcid":"0000-0002-9207-7579","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:09:58.338267Z","pmid":"36980794","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":[]}