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ResearchIn-Press PreviewGeneticsOncology Open Access | 10.1172/JCI164397

Human endogenous retrovirus onco-exaptation counters cancer cell senescence through Calbindin

Jan Attig,1 Judith Pape,1 Laura Doglio,1 Anastasiya Kazachenka,1 Eleonora Ottina,1 George R. Young,2 Katey S.S. Enfield,3 Iker Valle Aramburu,4 Kevin W. Ng,1 Nikhil Faulkner,1 William Bolland,1 Venizelos Papayannopoulos,4 Charles Swanton,3 and George Kassiotis1

1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

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1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

Find articles by Bolland, W. in: JCI | PubMed | Google Scholar

1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

Find articles by Papayannopoulos, V. in: JCI | PubMed | Google Scholar |

1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

Find articles by Swanton, C. in: JCI | PubMed | Google Scholar

1Department of Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

2Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom

3Department of Cancer Evolution and Genome Instability, The Francis Crick Institute, London, United Kingdom

4Antimicrobial Defence Laboratory, The Francis Crick Institute, London, United Kingdom

Find articles by Kassiotis, G. in: JCI | PubMed | Google Scholar

Published May 16, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI164397.
Copyright © 2023, Attig et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 16, 2023 - Version history
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Abstract

Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterizes most cancer types, linked with disease outcomes. However, the underlying processes are incompletely understood. We show that elevated transcription of HERVH proviruses predicts survival of lung squamous cell carcinoma (LUSC) and identify an isoform of CALB1, encoding Calbindin, ectopically driven by an upstream HERVH provirus under the control of KLF5, as the mediator of this effect. HERVH-CALB1 expression initiates in pre-invasive lesions and associates with their progression. Calbindin loss in LUSC cell lines impairs in vitro and in vivo growth and triggers senescence, consistent with a pro-tumor effect. However, Calbindin also directly controls the senescence-associated secretory phenotype (SASP), marked by secretion of CXCL8 and other neutrophil chemoattractants. In established carcinomas, CALB1-negative cancer cells become the dominant source of CXCL8, correlating with neutrophil infiltration and worse prognosis. Thus, HERVH-CALB1 expression in LUSC may display antagonistic pleiotropy, whereby the benefits of escaping senescence early during cancer initiation and clonal competition are offset by the prevention of SASP and pro-tumor inflammation at later stages.

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