Oncogenic ETS fusions promote DNA damage and proinflammatory responses via pericentromeric RNAs in extracellular vesicles
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 r...
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| Published in | The Journal of clinical investigation Vol. 134; no. 9; pp. 1 - 15 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Clinical Investigation
01.05.2024
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| Subjects | |
| Online Access | Get full text |
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| Abstract | 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 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 patients with EwS with metastatic disease. High human satellite 2 and 3 (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 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. |
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| AbstractList | 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
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 patients with EwS with metastatic disease. High human satellite 2 and 3 (
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 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.
Transcriptional activation of pericentromeric heterochromatin driven by EWS::FLI1 in Ewing sarcoma and TMPRSS2 fusion proteins in prostate cancer yield pathogenic RNAs, which transmit genotoxic stress. 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 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 patients with EwS with metastatic disease. High human satellite 2 and 3 (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 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. 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 HSAT2 and HSAT3 RNAs, together with UNE, 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 patients with EwS with metastatic disease. High human satellite 2 and 3 (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 o^HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBI<1 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. |
| Audience | Academic |
| Author | Minkovich, Alon Pachva, Manideep C Zaidi, Mark McKee, Trevor D Radvanyi, Laszlo Sorensen, Poul H Orlic-Milacic, Marija Ruzanov, Peter Zaidi, Syed H Thiel, Uwe Lapouble, Eve Langman, Sofya Peltekova, Vanya Burdach, Stefan Eg Zhang, Zhenbo Sharma, Manju McPherson, John D Stein, Lincoln D Cox, Michael E Evdokimova, Valentina Delattre, Olivier Gassmann, Hendrik Heisler, Lawrence E |
| AuthorAffiliation | 15 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada 5 Vancouver Prostate Centre, Vancouver, British Columbia, Canada 7 Pathomics Inc., Toronto, Ontario, Canada 1 Ontario Institute for Cancer Research, Toronto, Ontario, Canada 6 STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada 8 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada 3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada 4 Department of Pediatrics, Children’s Cancer Research Center, Kinderklinik München Schwabing, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany 11 Diversity and Plasticity of Childhood tumors, INSERM U830, Institut Curie Research Center, PSL Research University, Paris, France 12 Department of Immunology, University of Toronto, Toronto, Ontario, Canada 14 Institute of Pat |
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| Keywords | Innate immunity Inflammation |
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| Snippet | Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including... |
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| SubjectTerms | Animals Breast cancer Causes of Cell Line, Tumor Cell organelles Development and progression DNA DNA binding proteins DNA Damage Ewing's sarcoma Ewings sarcoma Extracellular vesicles Extracellular Vesicles - genetics Extracellular Vesicles - metabolism Fibroblasts Genetic aspects Genotoxicity Health aspects Heterochromatin Heterochromatin - genetics Heterochromatin - metabolism Humans Inflammation Inflammation - genetics Inflammation - metabolism Inflammation - pathology Male Malignancy Melanoma Metastases Metastasis Mice Oncogene Proteins, Fusion - genetics Oncogene Proteins, Fusion - metabolism Physiological aspects Plasma Plasma levels Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Proteins Proto-Oncogene Protein c-fli-1 - genetics Proto-Oncogene Protein c-fli-1 - metabolism RNA RNA, Neoplasm - genetics RNA, Neoplasm - metabolism RNA-Binding Protein EWS - genetics RNA-Binding Protein EWS - metabolism Sarcoma Sarcoma, Ewing - genetics Sarcoma, Ewing - immunology Sarcoma, Ewing - metabolism Sarcoma, Ewing - pathology Scientific equipment and supplies industry Senescence Transcription factors Transcriptional Regulator ERG - genetics Transcriptional Regulator ERG - metabolism Tumors |
| Title | Oncogenic ETS fusions promote DNA damage and proinflammatory responses via pericentromeric RNAs in extracellular vesicles |
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