Tumour exosome integrins determine organotropic metastasis

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, Caitlin Williams, Nadine Soplop, Kunihiro Uryu, Lindsay Pharmer, Tari King, Linda Bojmar, Alexander E. Davies, Yonathan Ararso, Tuo Zhang, Haiying Zhang, Jonathan Hernandez, Joshua M. Weiss, Vanessa D. Dumont-Cole, Kimberly Kramer, Leonard H. Wexler, Aru Narendran, Gary K. Schwartz, John H. Healey, Per Sandstrom, Knut Jørgen Labori, Elin H. Kure, Paul M. Grandgenett, Michael A. Hollingsworth, Maria de Sousa, Sukhwinder Kaur, Maneesh Jain, Kavita Mallya, Surinder K. Batra, William R. Jarnagin, Mary S. Brady, Oystein Fodstad, Volkmar Muller, Klaus Pantel, Andy J. Minn, Mina J. Bissell, Benjamin A. Garcia, Yibin Kang, Vinagolu K. Rajasekhar, Cyrus M. Ghajar, Irina Matei, Hector Peinado (), Jacqueline Bromberg () and David Lyden ()
Additional contact information
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
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
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
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
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
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
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
Oystein Fodstad: Norwegian Radium Hospital, Oslo University Hospital
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
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
Jacqueline Bromberg: Memorial Sloan Kettering Cancer Center
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

Nature, 2015, vol. 527, issue 7578, 329-335

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15756

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