{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:46:14Z","timestamp":1768527974028,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,8]]},"group-title":"Cancer Biology","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute\/National Institutes of Health","award":["R00CA218885"],"award-info":[{"award-number":["R00CA218885"]}]},{"name":"National Cancer Institute\/National Institutes of Health","award":["R37CA258730"],"award-info":[{"award-number":["R37CA258730"]}]},{"name":"National Cancer Institute\/National Institutes of Health","award":["R01CA288820"],"award-info":[{"award-number":["R01CA288820"]}]},{"name":"National Cancer Institute\/National Institutes of Health","award":["R01CA292949"],"award-info":[{"award-number":["R01CA292949"]}]},{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"crossref","award":["W81XWH-18-1-0411"],"award-info":[{"award-number":["W81XWH-18-1-0411"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"crossref","award":["W81XWH21-1-0520"],"award-info":[{"award-number":["W81XWH21-1-0520"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RR170050"],"award-info":[{"award-number":["RR170050"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RP220473"],"award-info":[{"award-number":["RP220473"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000892","name":"Prostate Cancer Foundation","doi-asserted-by":"crossref","award":["17YOUN12"],"award-info":[{"award-number":["17YOUN12"]}],"id":[{"id":"10.13039\/100000892","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Yale Cancer Center CCSG Pilot Grant","award":["P30CA016359"],"award-info":[{"award-number":["P30CA016359"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of pan-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, in specific lineages. By analyzing multi-omics data, including 39 HOX genes from over 80,000 RNA-seq samples across 114 cancer types, we discovered that HOX code expression robustly represents cancer cell lineages and reveals multiple previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying altered HOX patterns compared to non-plastic subtypes. Differential analysis further identified RUNX1T1 as a novel and consistent marker of plasticity, elevated across all three cancer types and correlating with HOX code and lineage-plastic marker genes. We validated these correlations in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and provided direct functional evidence that RUNX1T1 is required for lineage-plastic programs in prostate cancer. Using AI-based modeling, we identified NCOR\/HDAC as RUNX1T1 binding partners forming a co-repressor complex that regulates HOX codes and plasticity. Finally, pharmacologic HDAC inhibition selectively suppressed the growth of plastic cells, revealing a novel therapeutic vulnerability. These findings establish ectopic RUNX1T1 as a pan-cancer biomarker and critical mediator of lineage plasticity and identify the RUNX1T1\u2013HDAC complex as a druggable target.<\/jats:p>","DOI":"10.1101\/2025.10.07.681000","type":"posted-content","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:35:19Z","timestamp":1759955719000},"source":"Crossref","is-referenced-by-count":1,"title":["RUNX1T1-HDAC Reprogramming of the HOX Code Signaling Drives a Targetable Pan-Cancer Lineage Plasticity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9019-1739","authenticated-orcid":false,"given":"Yuyin","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4931-1403","authenticated-orcid":false,"given":"Siyuan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine Yijia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8397-311X","authenticated-orcid":false,"given":"Yaru","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaac Yi","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0955-0896","authenticated-orcid":false,"given":"Ping","family":"Mu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025101008350870000_2025.10.07.681000v1.1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-1423"},{"issue":"9","key":"2025101008350870000_2025.10.07.681000v1.2","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/s43018-022-00431-9","article-title":"Ectopic JAK-STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance","volume":"3","year":"2022","journal-title":"Nat Cancer"},{"key":"2025101008350870000_2025.10.07.681000v1.3","doi-asserted-by":"publisher","DOI":"10.2217\/pgs-2017-0039"},{"key":"2025101008350870000_2025.10.07.681000v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah4307"},{"key":"2025101008350870000_2025.10.07.681000v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah4199"},{"key":"2025101008350870000_2025.10.07.681000v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0554-0"},{"key":"2025101008350870000_2025.10.07.681000v1.7","doi-asserted-by":"crossref","unstructured":"Zhang, Z. , et al., Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer cell, 2020.","DOI":"10.1016\/j.ccell.2020.03.001"},{"key":"2025101008350870000_2025.10.07.681000v1.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat5749"},{"key":"2025101008350870000_2025.10.07.681000v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature03664"},{"key":"2025101008350870000_2025.10.07.681000v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002003"},{"key":"2025101008350870000_2025.10.07.681000v1.11","doi-asserted-by":"crossref","unstructured":"Li, X. , et al., Lineage plasticity and histological transformation: tumor histology as a spectrum. Cell Res, 2025.","DOI":"10.1038\/s41422-025-01180-x"},{"issue":"18","key":"2025101008350870000_2025.10.07.681000v1.12","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1158\/0008-5472.CAN-23-2260","article-title":"The Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer","volume":"83","year":"2023","journal-title":"Cancer Res"},{"key":"2025101008350870000_2025.10.07.681000v1.13","doi-asserted-by":"crossref","first-page":"215901","DOI":"10.1016\/j.canlet.2022.215901","article-title":"Lineage plasticity in prostate cancer: Looking beyond intrinsic alterations","volume":"548","year":"2022","journal-title":"Cancer Lett"},{"key":"2025101008350870000_2025.10.07.681000v1.14","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21763"},{"key":"2025101008350870000_2025.10.07.681000v1.15","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21349"},{"key":"2025101008350870000_2025.10.07.681000v1.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1405095"},{"key":"2025101008350870000_2025.10.07.681000v1.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1209096"},{"key":"2025101008350870000_2025.10.07.681000v1.18","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1715546"},{"issue":"2","key":"2025101008350870000_2025.10.07.681000v1.19","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1530\/ERC-20-0272","article-title":"Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview","volume":"28","year":"2021","journal-title":"Endocr Relat Cancer"},{"key":"2025101008350870000_2025.10.07.681000v1.20","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0225"},{"key":"2025101008350870000_2025.10.07.681000v1.21","first-page":"217430","article-title":"Prostate luminal cell plasticity and cancer","volume":"611","year":"2024","journal-title":"Cancer Lett"},{"key":"2025101008350870000_2025.10.07.681000v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2019.06.002"},{"key":"2025101008350870000_2025.10.07.681000v1.23","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0539"},{"key":"2025101008350870000_2025.10.07.681000v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-021-01982-4"},{"key":"2025101008350870000_2025.10.07.681000v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.10.033"},{"key":"2025101008350870000_2025.10.07.681000v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29963-5"},{"key":"2025101008350870000_2025.10.07.681000v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1719168115"},{"key":"2025101008350870000_2025.10.07.681000v1.28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-3571"},{"key":"2025101008350870000_2025.10.07.681000v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0340-z"},{"key":"2025101008350870000_2025.10.07.681000v1.30","unstructured":"Cyrta, J. , et al., Role of Specialized mSWI\/SNF Complexes in Prostate Cancer Lineage Plasticity. bioRxiv, 2020: p. 2020.03.06.949131."},{"key":"2025101008350870000_2025.10.07.681000v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00743-5"},{"issue":"4","key":"2025101008350870000_2025.10.07.681000v1.32","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s43018-021-00185-w","article-title":"EZH2 inhibition activates a dsRNA\u2013STING\u2013interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer","volume":"2","year":"2021","journal-title":"Nature Cancer"},{"key":"2025101008350870000_2025.10.07.681000v1.33","doi-asserted-by":"crossref","unstructured":"Jiang, Y. , et al., Notch as a Driver of Lineage Plasticity and Therapeutic Target in Enzalutamide-Resistant Prostate Cancer. bioRxiv, 2025.","DOI":"10.1101\/2025.05.26.656166"},{"key":"2025101008350870000_2025.10.07.681000v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.06.010"},{"key":"2025101008350870000_2025.10.07.681000v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-023-02890-5"},{"key":"2025101008350870000_2025.10.07.681000v1.36","doi-asserted-by":"crossref","unstructured":"Hubert, K.A. and D.M. Wellik , Hox genes in development and beyond. Development, 2023. 150(1).","DOI":"10.1242\/dev.192476"},{"issue":"1","key":"2025101008350870000_2025.10.07.681000v1.37","first-page":"23","article-title":"HOX genes: seductive science, mysterious mechanisms","volume":"75","year":"2006","journal-title":"Ulster Med J"},{"key":"2025101008350870000_2025.10.07.681000v1.38","doi-asserted-by":"crossref","unstructured":"Cheng, S.Y. , et al., Neuroendocrine prostate cancer has distinctive, non-prostatic HOX code that is represented by the loss of HOXB13 expression. Scientific Reports, 2021. 11(1).","DOI":"10.1038\/s41598-021-82472-1"},{"key":"2025101008350870000_2025.10.07.681000v1.39","doi-asserted-by":"publisher","DOI":"10.1002\/pros.24448"},{"key":"2025101008350870000_2025.10.07.681000v1.40","doi-asserted-by":"crossref","unstructured":"Li, L. , et al., Systematic Multi-Omics Investigation of Androgen Receptor Driven Gene Expression and Epigenetics changes in Prostate Cancer. bioRxiv, 2024.","DOI":"10.1101\/2024.07.22.604505"},{"key":"2025101008350870000_2025.10.07.681000v1.41","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2010.03568.x"},{"key":"2025101008350870000_2025.10.07.681000v1.42","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24481"},{"issue":"8","key":"2025101008350870000_2025.10.07.681000v1.43","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1038\/s41588-025-02265-4","article-title":"NKX2-1 drives neuroendocrine transdifferentiation of prostate cancer via epigenetic and 3D chromatin remodeling","volume":"57","year":"2025","journal-title":"Nat Genet"},{"key":"2025101008350870000_2025.10.07.681000v1.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216808"},{"issue":"1","key":"2025101008350870000_2025.10.07.681000v1.45","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/s41698-024-00667-x","article-title":"Unveiling novel double-negative prostate cancer subtypes through single-cell RNA sequencing analysis","volume":"8","year":"2024","journal-title":"NPJ Precis Oncol"},{"key":"2025101008350870000_2025.10.07.681000v1.46","doi-asserted-by":"crossref","unstructured":"Luo, Z. , S.K. Rhie , and P.J. Farnham , The Enigmatic HOX Genes: Can We Crack Their Code? Cancers (Basel), 2019. 11(3).","DOI":"10.3390\/cancers11030323"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.07.681000","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:45:19Z","timestamp":1768470319000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.10.07.681000"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":46,"URL":"https:\/\/doi.org\/10.1101\/2025.10.07.681000","relation":{},"subject":[],"published":{"date-parts":[[2025,10,8]]},"subtype":"preprint"}}