{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T20:54:38Z","timestamp":1788209678893,"version":"build-2803163510"},"reference-count":66,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T00:00:00Z","timestamp":1714521600000},"content-version":"vor","delay-in-days":36,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"CIHR","doi-asserted-by":"crossref","award":["FDN-143280"],"award-info":[{"award-number":["FDN-143280"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Goverment of Ontario, Cura Placida Children\u2019s Cancer Research Foundation grants","award":["501830041"],"award-info":[{"award-number":["501830041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,1]]},"abstract":"<jats:p>\n                    Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like\n                    <jats:italic>HSAT2<\/jats:italic>\n                    and\n                    <jats:italic>HSAT3<\/jats:italic>\n                    RNAs, together with\n                    <jats:italic>LINE<\/jats:italic>\n                    ,\n                    <jats:italic>SINE<\/jats:italic>\n                    ,\n                    <jats:italic>ERV,<\/jats:italic>\n                    and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (\n                    <jats:italic>HSAT2,3<\/jats:italic>\n                    ) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2\/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of\n                    <jats:italic>HSAT2,3<\/jats:italic>\n                    RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically,\n                    <jats:italic>HSAT2,3<\/jats:italic>\n                    -enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.\n                  <\/jats:p>","DOI":"10.1172\/jci169470","type":"journal-article","created":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T12:00:33Z","timestamp":1711454433000},"source":"Crossref","is-referenced-by-count":12,"title":["Oncogenic ETS fusions promote DNA damage and proinflammatory responses via pericentromeric RNAs in extracellular vesicles"],"prefix":"10.1172","volume":"134","author":[{"given":"Peter","family":"Ruzanov","sequence":"first","affiliation":[{"name":"Ontario Institute for Cancer Research, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Evdokimova","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manideep 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Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed H.","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanya","family":"Peltekova","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence E.","family":"Heisler","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manju","family":"Sharma","sequence":"additional","affiliation":[{"name":"Vancouver Prostate Centre, Vancouver, British Columbia, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Cox","sequence":"additional","affiliation":[{"name":"Vancouver Prostate Centre, Vancouver, British Columbia, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor D.","family":"McKee","sequence":"additional","affiliation":[{"name":"STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada."},{"name":"Pathomics Inc., Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Pathomics Inc., Toronto, Ontario, Canada."},{"name":"Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve","family":"Lapouble","sequence":"additional","affiliation":[{"name":"Unit\u00e9 G\u00e9n\u00e9tique Somatique (UGS), Institut Curie, Centre Hospitalier Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"McPherson","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, Toronto, Ontario, Canada."},{"name":"Department of Biochemistry and Molecular Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Delattre","sequence":"additional","affiliation":[{"name":"Unit\u00e9 G\u00e9n\u00e9tique Somatique (UGS), Institut Curie, Centre Hospitalier Paris, France."},{"name":"Diversity and Plasticity of Childhood tumors, INSERM U830, Institut Curie Research Center, PSL Research University, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laszlo","family":"Radvanyi","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, Toronto, Ontario, Canada."},{"name":"Department of Immunology, University of Toronto, Toronto, Ontario, 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