{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:39:54Z","timestamp":1791862794643,"version":"4.3.4"},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Anti\u2010androgen or castration therapies are the mainstay treatment for metastatic prostate cancers (PCa). Although effective at first, androgen\u2010dependent PCa (ADPC) universally develops therapy resistance, thereby evolving into an incurable disease called castration\u2010resistant PCa (CRPC). Currently, mechanisms underlying the emergence of CRPC from ADPC are largely unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used single\u2010cell RNA\u2010sequencing (scRNA\u2010Seq) to determine the transcription heterogeneity of a therapy\u2010na\u00efve ADPC cell line\u2014LNCaP and how it responded to the anti\u2010androgen drug, enzalutamide. Based on the results, we used single\u2010cell\/colony\u2010based cloning to isolate a pre\u2010enzalutamide cell subset, displaying low and\/or no expression of androgen receptor (AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that most LNCaP cells expressed enzalutamide\u2010target androgen receptor (AR+), while a small subpopulation (~10%) expressed low or no AR (AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      ). Gene set enrichment analysis (GSEA) revealed that AR\n                      <jats:sup>+<\/jats:sup>\n                      and AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      cells were enriched with significantly different gene expressions and signaling pathways. Unexpectedly, AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      cells displayed robust transcriptional response, including upregulations of genes and pathways involved in clinical CRPC. Next, we isolated AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      and AR\n                      <jats:sup>+<\/jats:sup>\n                      cells from enzalutamide\u2010na\u00efve LNCaP cells and functionally confirmed the enzalutamide\u2010resistant phenotype of AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      cells in vitro and in xenograft models in vivo. Through xenograft\u2010based single\u2010nucleus RNA\u2010Seq, we further found that the AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      cells were selected, while the AR\n                      <jats:sup>+<\/jats:sup>\n                      cells were de\u2010selected in vivo by enzalutamide. Also, we found that the selection and expansion of AR\n                      <jats:sup>low\/\u2212<\/jats:sup>\n                      clone were recapitulated in another enzalutamide\u2010resistant cell model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In summary, our single\u2010cell\u2010based sequencing and functional tests suggest a clonal selection and expansion model of enzalutamide resistance, in which the pretreatment AR\u2010low subpopulation is selected and expanded to confer treatment resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pros.24895","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T01:12:16Z","timestamp":1744333936000},"page":"888-899","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Understanding Enzalutamide\u2010Resistance Based on a Functional Single\u2010Cell Approach"],"prefix":"10.1002","volume":"85","author":[{"given":"Changhui","family":"Xue","sequence":"first","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7896-362X","authenticated-orcid":false,"given":"Hyun\u2010Kyung","family":"Ko","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasen","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Pittsenbarger","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucien","family":"Vu Dao","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyo","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Libmann","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Geng","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5532-2432","authenticated-orcid":false,"given":"David Z.","family":"Qian","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc801"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc4016"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1168175"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1405095"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0b013e32835105b3"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3678"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2018.22"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01174-3"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2019.03.003"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1404656111"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-020-00400-w"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.056"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam5355"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2956"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10798"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7303"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07411-7"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.049"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922207117"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13229"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-4968"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4053"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2014.25"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00370"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5659"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8456"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-1263"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.03.009"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2009.01.015"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-15-0137"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.724059"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2015.01.011"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.22650"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3186"}],"container-title":["The Prostate"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pros.24895","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T08:22:00Z","timestamp":1747038120000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pros.24895"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,10]]},"references-count":34,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1002\/pros.24895"],"URL":"https:\/\/doi.org\/10.1002\/pros.24895","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.10.20.619319","asserted-by":"object"}]},"ISSN":["0270-4137","1097-0045"],"issn-type":[{"value":"0270-4137","type":"print"},{"value":"1097-0045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,10]]},"assertion":[{"value":"2025-01-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}