{"doi":"10.1101/2021.11.08.467778","title":"Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition","abstract":"Abstract Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that enhance PCa progression. How tumor-induced bone formation enhances PCa progression is not known. We have previously shown that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted BMP4. Here, we show that EC-to-OSB transition leads to changes in the tumor microenvironment that increases the metastatic potential of PCa cells. We found that conditioned medium (CM) from EC-OSB hybrid cells increases the migration, invasion and survival of PC3-mm2 and C4-2B4 PCa cells. Quantitative mass spectrometry (iTRAQ) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced osteoblasts was confirmed by immunohistochemistry of MDA-PCa118b xenograft and human bone metastasis specimens. Mechanistically, BMP4 increases TNC expression in EC-OSB cells through the Smad1-Notch/Hey1 pathway. How TNC promotes PCa metastasis was next interrogated by in vitro and in vivo studies. In vitro studies showed that a TNC neutralizing antibody inhibits EC-OSB-CM-mediated PCa cell migration and survival. TNC knockdown decreased, while addition of recombinant TNC or TNC overexpression increased migration and anchorage-independent growth of PC3 or C4-2b cells. When injected orthotopically, PC3-mm2-shTNC clones decreased metastasis to bone, while C4-2b-TNC overexpressing cells increased metastasis to lymph nodes. TNC enhances PCa cell migration through α5β1 integrin-mediated YAP/TAZ inhibition. These studies elucidate that tumor-induced stromal reprogramming generates TNC that enhances PCa metastasis and suggest that TNC may be a target for PCa therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218047,"datarank":0.2390054872903336,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.03106133312235,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.03106133312235,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":655650,"name":"Song-Chang Lin","orcid":"0000-0003-1763-1303","position":1,"is_corresponding":false},{"id":655651,"name":"Guoyu Yu","orcid":"0000-0003-3030-5983","position":3,"is_corresponding":false},{"id":811038,"name":"Ming Zhu","orcid":"0000-0003-1916-8121","position":4,"is_corresponding":false},{"id":274888,"name":"Jian H. Song","orcid":"0000-0001-9252-1468","position":5,"is_corresponding":false},{"id":442084,"name":"Keith Rivera","orcid":"0000-0003-2979-9576","position":6,"is_corresponding":false},{"id":442085,"name":"Darryl Pappin","orcid":"0000-0002-8981-8401","position":7,"is_corresponding":false},{"id":70219,"name":"Christopher J. Logothetis","orcid":"0000-0002-6365-1711","position":8,"is_corresponding":false},{"id":490398,"name":"Theocharis Panaretakis","orcid":"0000-0001-5754-6950","position":9,"is_corresponding":false},{"id":274890,"name":"Guocan Wang","orcid":"0000-0002-8922-7249","position":10,"is_corresponding":false},{"id":744906,"name":"Li‐Yuan Yu‐Lee","orcid":"0000-0002-2353-406X","position":11,"is_corresponding":false},{"id":490397,"name":"Sue-Hwa Lin","orcid":"0000-0002-6122-4054","position":12,"is_corresponding":false},{"id":655649,"name":"Yu‐Chen Lee","orcid":"0000-0002-9510-3146","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:24.683898Z","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":[]}