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Adv."],"published-print":{"date-parts":[[2026,1,23]]},"abstract":"<jats:p>\n                    Subpopulations of cancer-associated fibroblast (CAF)\u2013like tumor cells deposit extracellular matrix (ECM) proteins that support Ewing sarcoma (EwS) progression and metastasis. We previously showed a hallmark of CAF-like EwS cells is their hybrid transcriptional state wherein the driver fusion oncogene, EWS::FLI1, maintains activation of proliferative programs but loses capacity to repress mesenchymal genes. Here, we studied primary patient tumors and cell line models to identify molecular drivers of this hybrid state. Our data reveal that hybrid EwS cells are induced and maintained by a transforming growth factor\u2013\u03b2 (TGF\u03b2) signaling positive feedback loop. Hybrid cells derepress\n                    <jats:italic toggle=\"yes\">TGFBR2<\/jats:italic>\n                    and up-regulate expression and secretion of TGF\u03b22 to sustain pathway activation and ECM deposition. Although TGF\u03b2 ligands can potently induce growth arrest in cells of epithelial origin, we show that TGF\u03b21 and TGF\u03b22 promote cell invasion of EwS cells without affecting proliferation. Thus, stroma-derived and tumor-derived TGF\u03b2 ligands induce and maintain hybrid EwS cells to promote pro-metastatic cell phenotypes.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ady0550","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T19:00:26Z","timestamp":1769022026000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Autocrine TGF\u03b22 enforces a transcriptionally hybrid cell state in Ewing sarcoma"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9643-457X","authenticated-orcid":true,"given":"Emma D.","family":"Wrenn","sequence":"first","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4345-762X","authenticated-orcid":true,"given":"Jacob C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April A.","family":"Apfelbaum","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer\/Boston Children\u2019s Cancer and Blood Disorders Center, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonah R.","family":"Valenti","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6398-5068","authenticated-orcid":true,"given":"Patricia A.","family":"Lipson","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."},{"name":"School of Medicine, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie I.","family":"Walter","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3717-5520","authenticated-orcid":true,"given":"Nicolas M.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6748-4595","authenticated-orcid":true,"given":"Aya","family":"Miyaki","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5269-7383","authenticated-orcid":true,"given":"Steven C.","family":"Chen","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5990-6534","authenticated-orcid":true,"given":"Jim M.","family":"Olson","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."},{"name":"Department of Pediatrics, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason P.","family":"Price","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."},{"name":"Department of Pediatrics, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3925-3243","authenticated-orcid":true,"given":"Kelly M.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2350-1540","authenticated-orcid":true,"given":"Elizabeth R.","family":"Lawlor","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer &amp; Blood Disorders Research, Seattle Children\u2019s Research Institute, Seattle, WA, USA."},{"name":"Department of Pediatrics, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-1067"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0225"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-01195-4"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.037"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2028910"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0003-x"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12040948"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.049"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-1111"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3422"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-020-00294-8"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.498"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","unstructured":"V. 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Gao, X. Y. He, X. S. Wu, Y. H. Huang, S. Toneyan, T. Ha, J. J. Ipsaro, P. K. Koo, L. Joshua-Tor, K. M. Bailey, M. Egeblad, C. R. Vakoc, ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation. Nat. Cell Biol. 25, 298\u2013308 (2023).","journal-title":"Nat. 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