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Tumour exosome integrins determine organotropic metastasis

Author

Listed:
  • Ayuko Hoshino

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Bruno Costa-Silva

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Tang-Long Shen

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    National Taiwan University)

  • Goncalo Rodrigues

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto)

  • Ayako Hashimoto

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    Faculty of Medicine, University of Tokyo)

  • Milica Tesic Mark

    (Proteomics Resource Center, The Rockefeller University)

  • Henrik Molina

    (Proteomics Resource Center, The Rockefeller University)

  • Shinji Kohsaka

    (Memorial Sloan Kettering Cancer Center)

  • Angela Di Giannatale

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Sophia Ceder

    (Karolinska Institutet)

  • Swarnima Singh

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Caitlin Williams

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Nadine Soplop

    (Electron Microscopy Resource Center (EMRC), Rockefeller University)

  • Kunihiro Uryu

    (Electron Microscopy Resource Center (EMRC), Rockefeller University)

  • Lindsay Pharmer

    (Breast Service, Memorial Sloan Kettering Cancer Center)

  • Tari King

    (Breast Service, Memorial Sloan Kettering Cancer Center)

  • Linda Bojmar

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    County Council of Östergötland, Faculty of Health Sciences, Linköping University)

  • Alexander E. Davies

    (Lawrence Berkeley National Laboratory, Berkeley)

  • Yonathan Ararso

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Tuo Zhang

    (Genomics Resources Core Facility, Weill Cornell Medicine)

  • Haiying Zhang

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Jonathan Hernandez

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    Memorial Sloan Kettering Cancer Center)

  • Joshua M. Weiss

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Vanessa D. Dumont-Cole

    (Memorial Sloan Kettering Cancer Center)

  • Kimberly Kramer

    (Memorial Sloan Kettering Cancer Center)

  • Leonard H. Wexler

    (Memorial Sloan Kettering Cancer Center)

  • Aru Narendran

    (Alberta Children’s Hospital)

  • Gary K. Schwartz

    (Columbia University School of Medicine)

  • John H. Healey

    (Orthopaedic Service, Memorial Sloan Kettering Cancer Center)

  • Per Sandstrom

    (County Council of Östergötland, Faculty of Health Sciences, Linköping University)

  • Knut Jørgen Labori

    (Oslo University Hospital)

  • Elin H. Kure

    (Institute for Cancer Research, Oslo University Hospital)

  • Paul M. Grandgenett

    (Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center)

  • Michael A. Hollingsworth

    (Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center)

  • Maria de Sousa

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto)

  • Sukhwinder Kaur

    (University of Nebraska Medical Center)

  • Maneesh Jain

    (University of Nebraska Medical Center)

  • Kavita Mallya

    (University of Nebraska Medical Center)

  • Surinder K. Batra

    (University of Nebraska Medical Center)

  • William R. Jarnagin

    (Memorial Sloan Kettering Cancer Center)

  • Mary S. Brady

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center)

  • Oystein Fodstad

    (Norwegian Radium Hospital, Oslo University Hospital
    Institute for Clinical Medicine, Faculty of Medicine, University of Oslo)

  • Volkmar Muller

    (University Medical Center)

  • Klaus Pantel

    (University Medical Center Hamburg-Eppendorf)

  • Andy J. Minn

    (Abramson Family Cancer Research Institute, University of Pennsylvania)

  • Mina J. Bissell

    (Lawrence Berkeley National Laboratory, Berkeley)

  • Benjamin A. Garcia

    (Perelman School of Medicine, University of Pennsylvania)

  • Yibin Kang

    (Princeton University
    Rutgers Cancer Institute of New Jersey)

  • Vinagolu K. Rajasekhar

    (Breast Medicine Service, Memorial Sloan Kettering Cancer Center)

  • Cyrus M. Ghajar

    (Fred Hutchinson Cancer Research Center)

  • Irina Matei

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine)

  • Hector Peinado

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    Microenvironment and Metastasis Laboratory, Spanish National Cancer Research Center (CNIO))

  • Jacqueline Bromberg

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • David Lyden

    (Children’s Cancer and Blood Foundation Laboratories, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medicine
    Memorial Sloan Kettering Cancer Center)

Abstract

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Suggested Citation

  • Ayuko Hoshino & Bruno Costa-Silva & Tang-Long Shen & Goncalo Rodrigues & Ayako Hashimoto & Milica Tesic Mark & Henrik Molina & Shinji Kohsaka & Angela Di Giannatale & Sophia Ceder & Swarnima Singh & C, 2015. "Tumour exosome integrins determine organotropic metastasis," Nature, Nature, vol. 527(7578), pages 329-335, November.
  • Handle: RePEc:nat:nature:v:527:y:2015:i:7578:d:10.1038_nature15756
    DOI: 10.1038/nature15756
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    Cited by:

    1. Zhiyuan Zheng & Ya-nan Li & Shanfen Jia & Mengting Zhu & Lijuan Cao & Min Tao & Jingting Jiang & Shenghua Zhan & Yongjing Chen & Ping-Jin Gao & Weiguo Hu & Ying Wang & Changshun Shao & Yufang Shi, 2021. "Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Bárbara Adem & Nuno Bastos & Carolina F. Ruivo & Sara Sousa-Alves & Carolina Dias & Patrícia F. Vieira & Inês A. Batista & Bruno Cavadas & Dieter Saur & José C. Machado & Dawen Cai & Sonia A. Melo, 2024. "Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    3. Ghulam Hassan Dar & Cláudia C. Mendes & Wei-Li Kuan & Alfina A. Speciale & Mariana Conceição & André Görgens & Inna Uliyakina & Miguel J. Lobo & Wooi F. Lim & Samir EL Andaloussi & Imre Mäger & Thomas, 2021. "GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. 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.
    5. Feng Xie & Xiaoxue Zhou & Peng Su & Heyu Li & Yifei Tu & Jinjin Du & Chen Pan & Xiang Wei & Min Zheng & Ke Jin & Liyan Miao & Chao Wang & Xuli Meng & Hans Dam & Peter Dijke & Long Zhang & Fangfang Zho, 2022. "Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Di-Ao Liu & Kai Tao & Bin Wu & Ziyan Yu & Malwina Szczepaniak & Matthew Rames & Changsong Yang & Tatyana Svitkina & Yueyao Zhu & Fengyuan Xu & Xiaolin Nan & Wei Guo, 2023. "A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Wolasse Manfouo Wilfred Quentin, 2024. "Exosomes as Mediators of Cancer Metastasis: Unraveling the ‘Seed and Soil’ Hypothesis," International Journal of Research and Scientific Innovation, International Journal of Research and Scientific Innovation (IJRSI), vol. 11(9), pages 1038-1046, September.

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