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ResearchIn-Press PreviewInflammation Open Access | 10.1172/JCI169470
1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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1Ontario Institute for Cancer Research, Toronto, Canada
2Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Canada
3Department of Pediatrics, Technical University of Munich, Munich, Germany
4Vancouver Prostate Center, Vancouver, Canada
5STTARR Innovation Center, University Health Network, Toronto, Canada
6Pathomics Inc., Toronto, Canada
7Somatic Genetic Unit, Curie Institute, Paris, France
8Department of Molecular Oncology, British Columbia Cancer Research Center, Vancouver, Germany
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Published March 26, 2024 - More info
Aberrant expression of 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 HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs) and are highly elevated in plasma of EwS patients with metastatic disease. High HSAT2,3 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 HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-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 which 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.