{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:35:27Z","timestamp":1785404127801,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,13]]},"group-title":"Bioinformatics","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["007442"],"award-info":[{"award-number":["007442"]}],"id":[{"id":"https:\/\/ror.org\/0060t0j89","id-type":"ROR","asserted-by":"publisher"}]},{"name":"US National Institute of Health","award":["R01CA270785"],"award-info":[{"award-number":["R01CA270785"]}]},{"name":"US National Institute of Health","award":["R37NS095733"],"award-info":[{"award-number":["R37NS095733"]}]},{"name":"US National Institute of Health","award":["R21NS133390"],"award-info":[{"award-number":["R21NS133390"]}]},{"name":"US National Institute of Health","award":["R21NS138661"],"award-info":[{"award-number":["R21NS138661"]}]},{"name":"US National Institute of Health","award":["R21NS142543"],"award-info":[{"award-number":["R21NS142543"]}]},{"award":["5K22CA258953"],"award-info":[{"award-number":["5K22CA258953"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,12]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>Single-cell transcriptomics transformed our understanding of cellular heterogeneity, yet cross-dataset comparison remains fundamentally limited by batch effects, technology differences, and inconsistent annotation frameworks. These challenges have impeded efforts to connect developmental programs with disease states which creates a critical gap for understanding pediatric cancers with suspected developmental origins. Here, we demonstrate that topic modeling, an unsupervised natural language processing technique, overcomes these barriers by learning transferable transcriptional genetic signatures that generalize across datasets, technologies, and biological contexts without requiring data integration. Applying this framework to over one million fetal cerebellar nuclei, we identify seven distinct topics that capture the developmental spectrum of rhombic lip progenitors through external granule layer (EGL) differentiation, including transitional states missed by conventional clustering. These topics transfer successfully across sequencing technologies (SPLiT-seq to sci-RNA-seq3), developmental timepoints, species (human to mouse), and from single-cell to bulk RNA sequencing of 876 medulloblastoma tumors. We reveal that Sonic hedgehog (SHH) medulloblastoma subtypes retain these topics, corresponding to distinct stages of EGL development. Our findings highlight that developmental timing at tumor initiation fundamentally shapes tumor biology, with immediate implications for subtype-specific therapeutic strategies in pediatric brain cancer. Our workflow establishes topic modeling as a scalable solution for mining expanding genomic atlases with broad applications across different datasets, technologies, and biological contexts.<\/jats:p>","DOI":"10.1101\/2025.11.12.687706","type":"posted-content","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T21:25:24Z","timestamp":1763069124000},"source":"Crossref","is-referenced-by-count":0,"title":["Transferable Transcriptional Topic Modeling Traces Medulloblastoma Subtypes to Distinct Cerebellar Developmental States"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1300-0774","authenticated-orcid":false,"given":"Ashmitha","family":"Rajendran","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics and Medical Education, University of Washington School of Medicine, Seattle, WA"},{"name":"Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2865-8683","authenticated-orcid":false,"given":"Parthiv","family":"Haldipur","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6661-3024","authenticated-orcid":false,"given":"Sonali","family":"Arora","sequence":"additional","affiliation":[{"name":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaustubh","family":"Grama","sequence":"additional","affiliation":[{"name":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saanvi S.","family":"Subramanian","sequence":"additional","affiliation":[{"name":"\u2075Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyre","family":"Merino-Galan","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Johnson","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5406-8911","authenticated-orcid":false,"given":"Kimberly A.","family":"Aldinger","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA"},{"name":"Department of Pediatrics, University of Washington, Seattle, WA, USA"},{"name":"Department of Neurology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Shendure","sequence":"additional","affiliation":[{"name":"Department of Genome Sciences, University of Washington, Seattle, WA, USA"},{"name":"Brotman Baty Institute for Precision Medicine, Seattle, WA, USA"},{"name":"Seattle Hub for Synthetic Biology, Seattle, WA, USA"},{"name":"Howard Hughes Medical Institute, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen 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