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Advanced HGSCs exhibit pronounced cellular heterogeneity, including a subset of cancer-propagating cells (CPCs, also known as cancer stem cells) that are highly tumorigenic and display stem cell-associated properties such as self-renewal and chemoresistance. In contrast, a substantial fraction of HGSC cells is non-tumorigenic. The role of these non-cancer-propagating cells (non-CPCs) and their relationship to CPCs remain poorly understood. Here, we demonstrate that neoplastic cells expressing the intermediate filament protein keratin 5 (KRT5) represent bona fide CPCs. KRT5\u207a cells form cancer organoids over successive passages, are tumorigenic in serial dilution xenograft assays, and are resistant to the antineoplastic agents, doxorubicin and cisplatin. Single-cell lineage-tracing experiments show that KRT5\u207a CPCs give rise to KRT5\u207b cells. KRT5\u207a and KRT5\u207b populations exhibit distinct gene expression profiles, with KRT5\u207b cells characterized by expression of\n                  <jats:italic>SPP1<\/jats:italic>\n                  , which encodes the secreted factor osteopontin (OPN). Treatment with OPN enhances HGSC organoid growth and chemoresistance, whereas\n                  <jats:italic>SPP1<\/jats:italic>\n                  knockdown reverses these effects. Together, these findings support a model in which HGSC contains two hierarchically related cell populations: KRT5\u207a, OPN-responsive CPCs and KRT5\u207b, non-tumorigenic cells that form a niche producing OPN. Targeting pathways that sustain both stem-like tumor cells and their supportive niche may enable reduced dosing of highly toxic chemotherapeutic agents while enhancing therapeutic efficacy in HGSC.\n                <\/jats:p>","DOI":"10.64898\/2026.01.28.702332","type":"posted-content","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T16:30:12Z","timestamp":1769790612000},"source":"Crossref","is-referenced-by-count":0,"title":["Keratin 5 marks cancer-propagating cells sustained by an osteopontin-producing niche in high-grade serous ovarian carcinoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9080-8737","authenticated-orcid":false,"given":"Mallikarjun","family":"Bidarimath","sequence":"first","affiliation":[{"name":"Department of Biomedical and Translational Sciences, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2093-6482","authenticated-orcid":false,"given":"Coulter Q.","family":"Ralston","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Translational Sciences, Cornell University, Ithaca, New York, USA"},{"name":"Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandini","family":"Bidarimath","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Translational Sciences, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M.","family":"Rose","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Translational Sciences, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darianna","family":"Colina","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Translational Sciences, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Schmoeckel","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig Maximilians University, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew K.","family":"Godwin","sequence":"additional","affiliation":[{"name":"Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Mayr","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Ludwig Maximilians University, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lora H.","family":"Ellenson","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3017-1399","authenticated-orcid":false,"given":"Andrea","family":"Flesken-Nikitin","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Translational Sciences, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3729-7982","authenticated-orcid":false,"given":"Alexander Yu.","family":"Nikitin","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Translational Sciences, Cornell University, Ithaca, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020511502517000_2026.01.28.702332v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pathol.4.110807.092246"},{"key":"2026020511502517000_2026.01.28.702332v1.2","doi-asserted-by":"crossref","unstructured":"Phuong DJ , Pirtz MG , Ralston CQ , Cosgrove BD , Schimenti JC , Flesken-Nikitin A , et al. 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