{"doi":"10.1101/2025.11.18.689150","title":"CDH3 as a Novel Therapeutic Target in Basal-like Double-Negative Prostate Cancer","abstract":"ABSTRACT Purpose Basal-like (also known as double-negative) prostate cancers are aggressive tumors that lack effective targeted therapies. We aimed to delineate the role of CDH3 (P-cadherin) in basal-like prostate cancer and evaluate CDH3-directed therapeutic strategies. Methods We integrated genetically engineered mouse models (GEMMs) of prostate cancer, bulk and single-cell transcriptomic analyses, and a suite of in vitro and in vivo experiments. CDH3 expression and associated signaling pathways were examined in Pten/Apc double-knockout mouse prostates and human datasets. Functional studies included antibody-drug conjugate (ADC) cytotoxicity assays and the development of chimeric antigen receptor (CAR) T cells targeting CDH3, tested in prostate cancer cell lines and xenograft models. Results Pten/Apc double deletion in prostate GEMMs led to highly aggressive tumors with markedly elevated CDH3 expression and enrichment of non-canonical WNT signaling components. Transcriptomic analyses of patient-derived prostate tumors confirmed that CDH3 is significantly upregulated in basal-like prostate cancer subtypes relative to luminal subtypes. Single-cell RNA sequencing revealed CDH3 expression predominantly in basal epithelial cells. Mechanistically, we found that active YAP1 signaling and a WNT5A-ROR2 non-canonical WNT axis drive CDH3 expression. Targeting CDH3 with a CDH3-specific ADC induced potent, antigen-dependent killing of CDH3⁺ prostate cancer cells in vitro and significantly suppressed tumor growth in in vivo metastatic prostate cancer models. Likewise, CDH3-targeted CAR T cells specifically recognized and lysed CDH3-expressing prostate tumor cells while sparing CDH3-negative cells, leading to tumor regression and improved survival in mouse models, especially when combined with PD-1 checkpoint blockade. Conclusions CDH3 is a key marker and functional driver of basal-like prostate cancer. Therapeutic strategies leveraging CDH3, including ADCs and CAR T cells, demonstrate strong preclinical efficacy, supporting the development of CDH3-targeted treatments to overcome resistance in aggressive prostate cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":581752,"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":0.9574,"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":805831,"name":"Shiyu Wang","orcid":"0000-0002-8201-8022","position":1,"is_corresponding":false},{"id":706113,"name":"Loan Duong","orcid":"0000-0003-4785-7194","position":2,"is_corresponding":false},{"id":1015834,"name":"Ziyu Zeng","orcid":"0000-0002-0587-241X","position":3,"is_corresponding":false},{"id":580601,"name":"Jing Yang","orcid":"0000-0002-2048-735X","position":4,"is_corresponding":false},{"id":995775,"name":"Yun Zhao","orcid":"0000-0002-4815-8881","position":5,"is_corresponding":false},{"id":449675,"name":"Sharif Rahmy","orcid":"0000-0002-7825-7186","position":6,"is_corresponding":false},{"id":469151,"name":"Shan Feng","orcid":"0000-0001-5860-9239","position":7,"is_corresponding":false},{"id":1375579,"name":"Ariana Arce","orcid":"0009-0006-8602-686X","position":8,"is_corresponding":false},{"id":230883,"name":"Lin Jia","orcid":"0009-0001-5820-663X","position":9,"is_corresponding":false},{"id":300846,"name":"Jun Wan","orcid":"0000-0001-9286-6562","position":10,"is_corresponding":false},{"id":537938,"name":"Liang Cheng","orcid":"0000-0001-6049-5293","position":11,"is_corresponding":false},{"id":302042,"name":"Xuemin Lu","orcid":"0009-0008-0060-8346","position":12,"is_corresponding":false},{"id":274882,"name":"Xin Lü","orcid":"0000-0002-0284-6478","position":13,"is_corresponding":false},{"id":419664,"name":"Guoqiang Liu","orcid":"0000-0001-6337-5350","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:58:51.328454Z","pmid":"41332717","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":[]}