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Chromosomal instability drives metastasis through a cytosolic DNA response

Author

Listed:
  • Samuel F. Bakhoum

    (Memorial Sloan Kettering Cancer Center
    Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Bryan Ngo

    (Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Ashley M. Laughney

    (Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center)

  • Julie-Ann Cavallo

    (Memorial Sloan Kettering Cancer Center
    Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Charles J. Murphy

    (Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Peter Ly

    (Ludwig Institute for Cancer Research, University of California San Diego)

  • Pragya Shah

    (Nancy E. and Peter C. Meinig School of Biomedical Engineering & Weill Institute for Cell and Molecular Biology, Cornell University)

  • Roshan K. Sriram

    (Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Thomas B. K. Watkins

    (The Francis Crick Institute)

  • Neil K. Taunk

    (Memorial Sloan Kettering Cancer Center)

  • Mercedes Duran

    (Memorial Sloan Kettering Cancer Center
    Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Chantal Pauli

    (Institute for Pathology and Molecular Pathology, University Hospital Zurich)

  • Christine Shaw

    (Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center)

  • Kalyani Chadalavada

    (Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center)

  • Vinagolu K. Rajasekhar

    (Memorial Sloan Kettering Cancer Center)

  • Giulio Genovese

    (The Broad Institute of Harvard and MIT, Cambridge)

  • Subramanian Venkatesan

    (UCL Cancer Institute)

  • Nicolai J. Birkbak

    (The Francis Crick Institute
    UCL Cancer Institute)

  • Nicholas McGranahan

    (The Francis Crick Institute
    UCL Cancer Institute)

  • Mark Lundquist

    (Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Quincey LaPlant

    (Memorial Sloan Kettering Cancer Center)

  • John H. Healey

    (Memorial Sloan Kettering Cancer Center)

  • Olivier Elemento

    (Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Christine H. Chung

    (Moffitt Cancer Center)

  • Nancy Y. Lee

    (Memorial Sloan Kettering Cancer Center)

  • Marcin Imielenski

    (Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

  • Gouri Nanjangud

    (Molecular Cytogenetics Core, Memorial Sloan Kettering Cancer Center)

  • Dana Pe’er

    (Computational Biology Program, Memorial Sloan Kettering Cancer Center)

  • Don W. Cleveland

    (Ludwig Institute for Cancer Research, University of California San Diego)

  • Simon N. Powell

    (Memorial Sloan Kettering Cancer Center)

  • Jan Lammerding

    (Nancy E. and Peter C. Meinig School of Biomedical Engineering & Weill Institute for Cell and Molecular Biology, Cornell University)

  • Charles Swanton

    (The Francis Crick Institute
    UCL Cancer Institute)

  • Lewis C. Cantley

    (Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine)

Abstract

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Suggested Citation

  • Samuel F. Bakhoum & Bryan Ngo & Ashley M. Laughney & Julie-Ann Cavallo & Charles J. Murphy & Peter Ly & Pragya Shah & Roshan K. Sriram & Thomas B. K. Watkins & Neil K. Taunk & Mercedes Duran & Chantal, 2018. "Chromosomal instability drives metastasis through a cytosolic DNA response," Nature, Nature, vol. 553(7689), pages 467-472, January.
  • Handle: RePEc:nat:nature:v:553:y:2018:i:7689:d:10.1038_nature25432
    DOI: 10.1038/nature25432
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    Cited by:

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    2. Rishi Kumar Nageshan & Raquel Ortega & Nevan Krogan & Julia Promisel Cooper, 2024. "Fate of telomere entanglements is dictated by the timing of anaphase midregion nuclear envelope breakdown," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Qiwei Wang & Johann S. Bergholz & Liya Ding & Ziying Lin & Sheheryar K. Kabraji & Melissa E. Hughes & Xiadi He & Shaozhen Xie & Tao Jiang & Weihua Wang & Jason J. Zoeller & Hye-Jung Kim & Thomas M. Ro, 2022. "STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Zikun Ma & Zhiyong Li & Yize Mao & Jingwei Ye & Zefu Liu & Yuzhao Wang & Chen Wei & Jun Cui & Zhuowei Liu & Xiaoyu Liang, 2023. "AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. W. Dean Pontius & Ellen S. Hong & Zachary J. Faber & Jeremy Gray & Craig D. Peacock & Ian Bayles & Katreya Lovrenert & Diana H. Chin & Berkley E. Gryder & Cynthia F. Bartels & Peter C. Scacheri, 2023. "Temporal chromatin accessibility changes define transcriptional states essential for osteosarcoma metastasis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Qian Zhu & Jinzhou Huang & Hongyang Huang & Huan Li & Peiqiang Yi & Jake A. Kloeber & Jian Yuan & Yuping Chen & Min Deng & Kuntian Luo & Ming Gao & Guijie Guo & Xinyi Tu & Ping Yin & Yong Zhang & Jun , 2021. "RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Tomoko Yamamori Morita & Jie Yu & Yukie Kashima & Ryo Kamata & Gaku Yamamoto & Tatsunori Minamide & Chiaki Mashima & Miyuki Yoshiya & Yuta Sakae & Toyohiro Yamauchi & Yumi Hakozaki & Shun-ichiro Kagey, 2023. "CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    8. Biaobin Jiang & Quanhua Mu & Fufang Qiu & Xuefeng Li & Weiqi Xu & Jun Yu & Weilun Fu & Yong Cao & Jiguang Wang, 2021. "Machine learning of genomic features in organotropic metastases stratifies progression risk of primary tumors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    9. Yu-Hsuan Chen & Han-Hsiun Chen & Won-Jing Wang & Hsin-Yi Chen & Wei-Syun Huang & Chien-Han Kao & Sin-Rong Lee & Nai Yang Yeat & Ruei-Liang Yan & Shu-Jou Chan & Kuen-Phon Wu & Ruey-Hwa Chen, 2023. "TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Ramona N. Moro & Uddipta Biswas & Suhas S. Kharat & Filip D. Duzanic & Prosun Das & Maria Stavrou & Maria C. Raso & Raimundo Freire & Arnab Ray Chaudhuri & Shyam K. Sharan & Lorenza Penengo, 2023. "Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. Francesca Mateo & Zhengcheng He & Lin Mei & Gorka Ruiz de Garibay & Carmen Herranz & Nadia García & Amanda Lorentzian & Alexandra Baiges & Eline Blommaert & Antonio Gómez & Oriol Mirallas & Anna Garri, 2022. "Modification of BRCA1-associated breast cancer risk by HMMR overexpression," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    12. Yaling Dou & Rui Chen & Siyao Liu & Yi-Tsang Lee & Ji Jing & Xiaoxuan Liu & Yuepeng Ke & Rui Wang & Yubin Zhou & Yun Huang, 2023. "Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    13. Johanna Zerbib & Marica Rosaria Ippolito & Yonatan Eliezer & Giuseppina Feudis & Eli Reuveni & Anouk Savir Kadmon & Sara Martin & Sonia Viganò & Gil Leor & James Berstler & Julia Muenzner & Michael Mü, 2024. "Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    14. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    15. Kate M. MacDonald & Shirony Nicholson-Puthenveedu & Maha M. Tageldein & Sarika Khasnis & Cheryl H. Arrowsmith & Shane M. Harding, 2023. "Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    16. Jimyung Seo & HyunSeok Kim & Kyoung Il Min & Changgon Kim & Yongsoo Kwon & Zhenlong Zheng & Yusung Kim & Hyung-Soon Park & Young Seok Ju & Mi Ryung Roh & Kee Yang Chung & Joon Kim, 2022. "Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Mei Zhao & Tianxiao Wang & Frederico O. Gleber-Netto & Zhen Chen & Daniel J. McGrail & Javier A. Gomez & Wutong Ju & Mayur A. Gadhikar & Wencai Ma & Li Shen & Qi Wang & Ximing Tang & Sen Pathak & Mari, 2024. "Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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