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Here, we establish a framework to resolve state\u2013specific genetic vulnerabilities by integrating single\u2013cell multiomics (RNA and ATAC) with pooled CRISPR\u2013Cas9 screening across a large panel of patient\u2013derived organoids (PDOs) from castrate\u2013resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). We generate a single\u2013cell multiome atlas spanning &gt;190,000 cells across 22 PDOs, defining seven lineage states\u2014including intermediate and plastic populations not resolved by bulk profiling\u2014and demonstrate that these lineage programs robustly classify independent transcriptomic datasets from prostate cancer patient tumors. By systematically coupling this atlas to subtype\u2013resolved CRISPR screens, we construct a functional dependency map linking cell state in heterogeneous 3D human tumor models. We show that intratumoral heterogeneity fundamentally reshapes the interpretation of gene essentiality, whereby gene\u2013level depletion reflects the composite behavior of co\u2013existing subpopulations, and identify a general principle in which resistant \u201climiting\u201d populations disproportionately determine aggregate fitness effects. This framework reveals both canonical and previously unrecognized lineage\u2013restricted dependencies within highly plastic tumor and NEPC states, including a therapeutically targetable dependency on the aryl hydrocarbon receptor (AHR) in a novel hybrid stem\u2013like\/ASCL1 population. Together, these data establish an extensive multi\u2013dimensional prostate cancer resource, identify novel lineage\u2013resolved biology, and provide a generalizable strategy for interpreting functional genomics in heterogeneous human tumors.<\/jats:p>","DOI":"10.64898\/2026.05.07.723570","type":"posted-content","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T05:45:18Z","timestamp":1778305518000},"source":"Crossref","is-referenced-by-count":1,"title":["Dependencies in heterogeneous, lineage plastic patient\u2013derived prostate cancer organoids revealed through integrated single\u2013cell multiomics and CRISPR screening"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1592-2932","authenticated-orcid":false,"given":"Samir","family":"Zaidi","sequence":"first","affiliation":[{"name":"Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"B\u00fcttner","sequence":"additional","affiliation":[{"name":"Calico Life Sciences LLC, South San Francisco, CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiran","family":"Feng","sequence":"additional","affiliation":[{"name":"Cancer Epigenetics Institute, Nuclear Dynamics & Cancer Program Fox Chase Cancer Center, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Baxter","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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