{"doi":"10.1101/2023.07.18.549585","title":"NSD2 maintains lineage plasticity and castration-resistance in neuroendocrine prostate cancer","abstract":"Summary The clinical use of potent androgen receptor (AR) inhibitors has promoted the emergence of novel subtypes of metastatic castration-resistant prostate cancer (mCRPC), including neuroendocrine prostate cancer (CRPC-NE), which is highly aggressive and lethal 1 . These mCRPC subtypes display increased lineage plasticity and often lack AR expression 2–5 . Here we show that neuroendocrine differentiation and castration-resistance in CRPC-NE are maintained by the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2) 6 , which catalyzes histone H3 lysine 36 dimethylation (H3K36me2). We find that organoid lines established from genetically-engineered mice 7 recapitulate key features of human CRPC-NE, and can display transdifferentiation to neuroendocrine states in culture. CRPC-NE organoids express elevated levels of NSD2 and H3K36me2 marks, but relatively low levels of H3K27me3, consistent with antagonism of EZH2 activity by H3K36me2. Human CRPC-NE but not primary NEPC tumors expresses high levels of NSD2, consistent with a key role for NSD2 in lineage plasticity, and high NSD2 expression in mCRPC correlates with poor survival outcomes. Notably, CRISPR/Cas9 targeting of NSD2 or expression of a dominant-negative oncohistone H3.3K36M mutant results in loss of neuroendocrine phenotypes and restores responsiveness to the AR inhibitor enzalutamide in mouse and human CRPC-NE organoids and grafts. Our findings indicate that NSD2 inhibition can reverse lineage plasticity and castration-resistance, and provide a potential new therapeutic target for CRPC-NE.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391045,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9485,"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":347863,"name":"Alessandro Vasciaveo","orcid":"0000-0003-0205-9869","position":1,"is_corresponding":false},{"id":1163322,"name":"D Karagiannis","orcid":"0000-0002-4927-0816","position":2,"is_corresponding":false},{"id":313749,"name":"Zhen Sun","orcid":"0000-0001-9515-1925","position":3,"is_corresponding":false},{"id":163060,"name":"Xiao CHEN","orcid":null,"position":4,"is_corresponding":false},{"id":1163811,"name":"Fabio Socciarelli","orcid":null,"position":5,"is_corresponding":false},{"id":747864,"name":"Ziv Frankenstein","orcid":null,"position":6,"is_corresponding":false},{"id":319944,"name":"Min Zou","orcid":"0000-0003-0726-1003","position":7,"is_corresponding":false},{"id":383407,"name":"Tania Pannellini","orcid":"0000-0002-0224-9921","position":8,"is_corresponding":false},{"id":259330,"name":"Yu Chen","orcid":"0000-0002-0171-3884","position":9,"is_corresponding":false},{"id":393087,"name":"Kevin Gardner","orcid":"0000-0001-8018-4353","position":10,"is_corresponding":false},{"id":261869,"name":"Brian D. Robinson","orcid":"0000-0001-5374-890X","position":11,"is_corresponding":false},{"id":13272,"name":"Johann S. De Bono","orcid":"0000-0002-2034-595X","position":12,"is_corresponding":false},{"id":319950,"name":"Cory Abate‐Shen","orcid":"0000-0002-5021-0570","position":13,"is_corresponding":false},{"id":13152,"name":"Mark A. Rubin","orcid":"0000-0002-8321-9950","position":14,"is_corresponding":false},{"id":35291,"name":"Massimo Loda","orcid":"0000-0001-9674-8379","position":15,"is_corresponding":false},{"id":50790,"name":"Charles L. Sawyers","orcid":"0000-0003-4955-6475","position":16,"is_corresponding":false},{"id":19046,"name":"Andrea Califano","orcid":"0000-0003-4742-3679","position":17,"is_corresponding":false},{"id":284386,"name":"Chao Lü","orcid":"0000-0003-0982-8122","position":18,"is_corresponding":false},{"id":261873,"name":"Michael M. Shen","orcid":"0000-0002-4042-1657","position":19,"is_corresponding":false},{"id":1163321,"name":"Jia J. Li","orcid":"0000-0003-3676-5657","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-19T01:18:42.653719Z","pmid":"37502956","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":[]}