{"doi":"10.18632/oncotarget.28758","title":"Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer","abstract":"// Aiden Deacon 1 , 4 , Ava Gustafson 1 , 4 , Allison Makovec 1 , 4 , Ella Boytim 1 , 4 , Gabriella von Dohlen 1 , 4 , David Moline 1 , 4 , Elin Kairies 2 , Sam Kellen 1 , 4 , Khalid Ishani 1 , 4 , Megan L. Ludwig 3 , Emily John 1 , 4 , Alexis Anike 1 , 4 , Hai Dang Nguyen 3 , 4 , Scott M. Dehm 1 , 4 , Justin M. Drake 1 , 3 , Emmanuel S. Antonarakis 1 , 4 and Justin Hwang 1 , 4 1 Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA 2 Cornell College, Mount Vernon, IA 52314, USA 3 Department of Pharmacology, University of Minnesota- Twin Cities, Minneapolis, MN 55455, USA 4 Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA Correspondence to: Justin Hwang, email: jhwang@umn.edu Keywords: RSPO2; prostate cancer; Wnt signaling; genomics; therapeutics Received: March 18, 2025     Accepted: July 16, 2025     Published: July 25, 2025 Copyright: © 2025 Deacon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT This study investigates the R-spondin family of genes ( RSPO1/2/3/4 ), a group of secreted proteins that act as Wnt regulators, and their subsequent role in advanced prostate cancer (PC). When evaluating transcriptomic data from primary and metastatic PC patients, we found that alterations in RSPO2 were more prevalent than in other RSPO family members or Wnt-regulating genes APC and CTNNB1 . Further, we found that RSPO2 alterations in PCs were significantly associated with worse disease-free survival. Through our in silico modeling, RSPO2 exhibited strong positive associations with genes regulating epithelial-mesenchymal transition (EMT) and double-negative prostate cancer (DNPC), but had negative correlations with androgen receptor (AR) and AR-associated genes. Furthermore, 3D modeling of RSPO2 revealed structural differences between itself and other RSPOs. In cell lines, RSPO2 overexpression caused up-regulation of EMT pathways, including EMT-regulatory transcription factors ZEB1, ZEB2, and TWIST1 . Conversely, this was not observed when CTNNB1 was overexpressed in the same models. These findings highlight that, in PC, RSPO2 functions as a unique member of the R-spondin family by promoting genes and signaling pathways associated with aggressive PC, and RSPO2 amplifications are associated with poor outcomes in PC patients.","journal":"Oncotarget","year":2025,"id":545600,"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":0.9544,"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":1267173,"name":"Ava Gustafson","orcid":null,"position":1,"is_corresponding":false},{"id":1219370,"name":"Allison Makovec","orcid":"0009-0008-2487-9079","position":2,"is_corresponding":false},{"id":1237727,"name":"Ella Boytim","orcid":"0009-0007-8062-6431","position":3,"is_corresponding":false},{"id":1436877,"name":"Gabriella von Dohlen","orcid":null,"position":4,"is_corresponding":false},{"id":1281926,"name":"David Moline","orcid":null,"position":5,"is_corresponding":false},{"id":1436878,"name":"Elin Kairies","orcid":null,"position":6,"is_corresponding":false},{"id":1436879,"name":"Sam Kellen","orcid":null,"position":7,"is_corresponding":false},{"id":1402010,"name":"Khalid Ishani","orcid":"0000-0003-1579-191X","position":8,"is_corresponding":false},{"id":590383,"name":"Megan Ludwig","orcid":"0000-0003-3133-3679","position":9,"is_corresponding":false},{"id":1381162,"name":"Emily John","orcid":null,"position":10,"is_corresponding":false},{"id":1436880,"name":"Alexis Anike","orcid":null,"position":11,"is_corresponding":false},{"id":271006,"name":"Hai Dang Nguyen","orcid":"0000-0002-4200-8778","position":12,"is_corresponding":false},{"id":292251,"name":"Scott M. Dehm","orcid":"0000-0002-7827-5579","position":13,"is_corresponding":false},{"id":351743,"name":"Justin M. Drake","orcid":"0000-0002-8329-7748","position":14,"is_corresponding":false},{"id":272258,"name":"Emmanuel S. Antonarakis","orcid":"0000-0003-0031-9655","position":15,"is_corresponding":false},{"id":351741,"name":"Justin H. Hwang","orcid":"0000-0003-1686-7103","position":16,"is_corresponding":false},{"id":1402595,"name":"Aiden Deacon","orcid":null,"position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-19T02:53:23.001995Z","pmid":"40711886","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":[]}