{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T21:58:21Z","timestamp":1778536701088,"version":"3.51.4"},"posted":{"date-parts":[[2026,1,9]]},"group-title":"Oncology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Aggressive variant prostate cancer (AVPC) is a lethal subtype of prostate cancer characterized by its androgen independence, resistance to chemotherapy, and display of neuroendocrine features which can emerge either de novo or via transformation after a prior diagnosis of adenocarcinoma. The poor clinical outcomes in patients with AVPC are associated with its profound molecular heterogeneity. In this study, we analyzed 23 consecutive AVPC cases treated at a dedicated small-cell clinic (2017\u20132025) using clinicogenomic and transcriptomic profiling. Transformed AVPC exhibited significantly shorter overall survival times than de novo AVPC (11.8 vs 26.0 months, P &lt; 0.001). Integrative genomic analyses identified residual androgen signaling in subsets of cases harboring neuroendocrine lineage programs, highlighting a decoupling of lineage identity and morphology. To facilitate mechanistic and pharmacologic studies, we established NCI-LYM-1, a patient-derived organoid\/PDX from an AR-negative, ASCL1+\/SYP+ lymph node metastasis, which faithfully recapitulates the donor tumor\u2019s molecular and phenotypic features. Short- and long-read whole-genome sequencing combined with optical genome mapping identified biallelic inactivation of\n                  <jats:italic>PTEN<\/jats:italic>\n                  ,\n                  <jats:italic>TP53<\/jats:italic>\n                  ,\n                  <jats:italic>RB1<\/jats:italic>\n                  and\n                  <jats:italic>BRCA2<\/jats:italic>\n                  as potential drivers, demonstrating clonal concordance with circulating tumor DNA from the original patient donor. Pathway and perturbation analyses suggested that NCI-LYM-1 harbored a strong dependency on apoptotic pathways, which was confirmed by\n                  <jats:italic>in vitro<\/jats:italic>\n                  organoid testing with the BCL-2\/BCL-xL inhibitor navitoclax (IC\n                  <jats:sub>50<\/jats:sub>\n                  : 0.27 \u00b5M) and the MCL-1 inhibitor AZD-5991 (IC\n                  <jats:sub>50<\/jats:sub>\n                  : 0.060 \u00b5M). Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies.\n                <\/jats:p>","DOI":"10.64898\/2026.01.07.26343520","type":"posted-content","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T10:35:11Z","timestamp":1767954911000},"source":"Crossref","is-referenced-by-count":1,"title":["Molecular decoupling of lineage identity and morphology in aggressive variant prostate cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4520-4694","authenticated-orcid":false,"given":"Chennan","family":"Li","sequence":"first","affiliation":[{"name":"Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6739-5463","authenticated-orcid":false,"given":"JuanJuan","family":"Yin","sequence":"additional","affiliation":[{"name":"Genitourinary 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