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Title: Tumour exosome integrins determine organotropic metastasis

Abstract

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. In this paper, 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 α 6β 4 and α 6β 1 were associated with lung metastasis, while exosomal integrin α vβ 5 was linked to liver metastasis. Targeting the integrins α 6β 4 and α vβ 5 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. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Authors:
 [1];  [1];  [2];  [3];  [4];  [5];  [5];  [6];  [1];  [7];  [1];  [1];  [8];  [8];  [9];  [9];  [10];  [11];  [1];  [12] more »;  [1];  [13];  [1];  [14];  [14];  [14];  [15];  [16];  [17];  [18];  [19];  [20];  [21];  [21];  [3];  [22];  [22];  [22];  [22];  [23];  [24];  [25];  [26];  [27];  [28];  [11];  [29];  [30];  [31];  [32];  [1];  [33];  [34];  [35] « less
  1. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center
  2. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; National Taiwan Univ., Taipei (Taiwan). Dept. of Plant Pathology and Microbiology. Center for Biotechnology
  3. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; Univ. of Porto (Portugal). Abel Salazar Biomedical Sciences Inst. Graduate Program in Areas of Basic and Applied Biology
  4. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; Univ. of Tokyo (Japan). Faculty of Medicine. Dept. of Obstetrics and Gynecology
  5. Rockefeller Univ., New York, NY (United States). Proteomics Resource Center
  6. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Pathology
  7. Karolinska Inst., Stockholm (Sweden). Dept. of Oncology and Pathology
  8. Rockefeller Univ., New York, NY (United States). Electron Microscopy Resource Center (EMRC)
  9. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Breast Service. Dept. of Surgery
  10. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; Linkoping Univ. (Sweden). Faculty of Health Sciences. Dept. of Clinical and Experimental Medicine. Dept. of Surgery
  11. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  12. Weill Cornell Medicine, New York, NY (United States). Genomics Resources Core Facility
  13. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Surgery
  14. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Pediatrics
  15. Alberta Children's Hospital, Calgary, AB (Canada). Division of Pediatric Oncology
  16. Columbia Univ., New York, NY (United States). School of Medicine. Division of Hematology/Oncology
  17. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Orthopaedic Service. Dept. of Surgery
  18. Linkoping Univ. (Sweden). Faculty of Health Sciences. Dept. of Clinical and Experimental Medicine. Dept. of Surgery
  19. Oslo Univ. Hospital (Norway). Dept. of Hepato-Pancreato-Biliary Surgery
  20. Oslo Univ. Hospital (Norway). Dept. of Cancer Genetics. Inst. for Cancer Research
  21. Univ. of Nebraska Medical Center, Omaha, NE (United States). Eppley Inst. for Research in Cancer and Allied Diseases
  22. Univ. of Nebraska Medical Center, Omaha, NE (United States). Dept. of Biochemistry and Molecular Biology
  23. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Surgery
  24. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Gastric and Mixed Tumor Service. Dept. of Surgery
  25. Oslo Univ. Hospital (Norway). Dept. of Tumor Biology. Norwegian Radium Hospital; Univ. of Oslo (Norway). Inst. for Clinical Medicine. Faculty of Medicine
  26. Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Gynecology
  27. Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Tumor Biology
  28. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Radiation Oncology. Abramson Family Cancer Research Inst.
  29. Univ. of Pennsylvania, Philadelphia, PA (United States). Dept. of Biochemistry and Biophysics. Perelman School of Medicine
  30. Princeton Univ., NJ (United States). Dept. of Molecular Biology; Rutgers Cancer Inst. of New Jersey, New Brunswick, NJ (United States)
  31. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Breast Medicine Service. Dept. of Medicine
  32. Fred Hutchinson Cancer Research Center, Seattle, WA (United States)
  33. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; Spanish National Cancer Research Center (CNIO), Madrid (Spain). Microenvironment and Metastasis Lab. Dept. of Molecular Oncology
  34. Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Medicine; Weill Cornell Medicine, New York, NY (United States). Dept. of Medicine
  35. Weill Cornell Medicine, New York, NY (United States). Children's Cancer and Blood Foundation Lab. Dept. of Pediatrics. Dept. of Cell and Developmental Biology. Drukier Inst. for Children's Health. Meyer Cancer Center; Memorial Sloan Kettering Cancer Center, New York, NY (United States). Dept. of Pediatrics
Publication Date:
Research Org.:
Weill Cornell Medicine, New York, NY (United States); Memorial Sloan Kettering Cancer Center, New York, NY (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States); USDOD; Ministry of Science and Technology (Taiwan)
OSTI Identifier:
1378654
Grant/Contract Number:  
AC02-05CH11231; P30 CA008748; U01-CA169538; R01-CA169416; W81XWH-13-10249; W81XWH-13-1-0425; 101-2918-I-002-016
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 527; Journal Issue: 7578; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; metastasis; cancer microenvironment; mechanisms of disease

Citation Formats

Hoshino, Ayuko, Costa-Silva, Bruno, Shen, Tang-Long, Rodrigues, Goncalo, Hashimoto, Ayako, Tesic Mark, Milica, Molina, Henrik, Kohsaka, Shinji, Di Giannatale, Angela, Ceder, Sophia, Singh, Swarnima, Williams, Caitlin, Soplop, Nadine, Uryu, Kunihiro, Pharmer, Lindsay, King, Tari, Bojmar, Linda, Davies, Alexander E., Ararso, Yonathan, Zhang, Tuo, Zhang, Haiying, Hernandez, Jonathan, Weiss, Joshua M., Dumont-Cole, Vanessa D., Kramer, Kimberly, Wexler, Leonard H., Narendran, Aru, Schwartz, Gary K., Healey, John H., Sandstrom, Per, Jørgen Labori, Knut, Kure, Elin H., Grandgenett, Paul M., Hollingsworth, Michael A., de Sousa, Maria, Kaur, Sukhwinder, Jain, Maneesh, Mallya, Kavita, Batra, Surinder K., Jarnagin, William R., Brady, Mary S., Fodstad, Oystein, Muller, Volkmar, Pantel, Klaus, Minn, Andy J., Bissell, Mina J., Garcia, Benjamin A., Kang, Yibin, Rajasekhar, Vinagolu K., Ghajar, Cyrus M., Matei, Irina, Peinado, Hector, Bromberg, Jacqueline, and Lyden, David. Tumour exosome integrins determine organotropic metastasis. United States: N. p., 2015. Web. doi:10.1038/nature15756.
Hoshino, Ayuko, Costa-Silva, Bruno, Shen, Tang-Long, Rodrigues, Goncalo, Hashimoto, Ayako, Tesic Mark, Milica, Molina, Henrik, Kohsaka, Shinji, Di Giannatale, Angela, Ceder, Sophia, Singh, Swarnima, Williams, Caitlin, Soplop, Nadine, Uryu, Kunihiro, Pharmer, Lindsay, King, Tari, Bojmar, Linda, Davies, Alexander E., Ararso, Yonathan, Zhang, Tuo, Zhang, Haiying, Hernandez, Jonathan, Weiss, Joshua M., Dumont-Cole, Vanessa D., Kramer, Kimberly, Wexler, Leonard H., Narendran, Aru, Schwartz, Gary K., Healey, John H., Sandstrom, Per, Jørgen Labori, Knut, Kure, Elin H., Grandgenett, Paul M., Hollingsworth, Michael A., de Sousa, Maria, Kaur, Sukhwinder, Jain, Maneesh, Mallya, Kavita, Batra, Surinder K., Jarnagin, William R., Brady, Mary S., Fodstad, Oystein, Muller, Volkmar, Pantel, Klaus, Minn, Andy J., Bissell, Mina J., Garcia, Benjamin A., Kang, Yibin, Rajasekhar, Vinagolu K., Ghajar, Cyrus M., Matei, Irina, Peinado, Hector, Bromberg, Jacqueline, & Lyden, David. Tumour exosome integrins determine organotropic metastasis. United States. doi:10.1038/nature15756.
Hoshino, Ayuko, Costa-Silva, Bruno, Shen, Tang-Long, Rodrigues, Goncalo, Hashimoto, Ayako, Tesic Mark, Milica, Molina, Henrik, Kohsaka, Shinji, Di Giannatale, Angela, Ceder, Sophia, Singh, Swarnima, Williams, Caitlin, Soplop, Nadine, Uryu, Kunihiro, Pharmer, Lindsay, King, Tari, Bojmar, Linda, Davies, Alexander E., Ararso, Yonathan, Zhang, Tuo, Zhang, Haiying, Hernandez, Jonathan, Weiss, Joshua M., Dumont-Cole, Vanessa D., Kramer, Kimberly, Wexler, Leonard H., Narendran, Aru, Schwartz, Gary K., Healey, John H., Sandstrom, Per, Jørgen Labori, Knut, Kure, Elin H., Grandgenett, Paul M., Hollingsworth, Michael A., de Sousa, Maria, Kaur, Sukhwinder, Jain, Maneesh, Mallya, Kavita, Batra, Surinder K., Jarnagin, William R., Brady, Mary S., Fodstad, Oystein, Muller, Volkmar, Pantel, Klaus, Minn, Andy J., Bissell, Mina J., Garcia, Benjamin A., Kang, Yibin, Rajasekhar, Vinagolu K., Ghajar, Cyrus M., Matei, Irina, Peinado, Hector, Bromberg, Jacqueline, and Lyden, David. Wed . "Tumour exosome integrins determine organotropic metastasis". United States. doi:10.1038/nature15756. https://www.osti.gov/servlets/purl/1378654.
@article{osti_1378654,
title = {Tumour exosome integrins determine organotropic metastasis},
author = {Hoshino, Ayuko and Costa-Silva, Bruno and Shen, Tang-Long and Rodrigues, Goncalo and Hashimoto, Ayako and Tesic Mark, Milica and Molina, Henrik and Kohsaka, Shinji and Di Giannatale, Angela and Ceder, Sophia and Singh, Swarnima and Williams, Caitlin and Soplop, Nadine and Uryu, Kunihiro and Pharmer, Lindsay and King, Tari and Bojmar, Linda and Davies, Alexander E. and Ararso, Yonathan and Zhang, Tuo and Zhang, Haiying and Hernandez, Jonathan and Weiss, Joshua M. and Dumont-Cole, Vanessa D. and Kramer, Kimberly and Wexler, Leonard H. and Narendran, Aru and Schwartz, Gary K. and Healey, John H. and Sandstrom, Per and Jørgen Labori, Knut and Kure, Elin H. and Grandgenett, Paul M. and Hollingsworth, Michael A. and de Sousa, Maria and Kaur, Sukhwinder and Jain, Maneesh and Mallya, Kavita and Batra, Surinder K. and Jarnagin, William R. and Brady, Mary S. and Fodstad, Oystein and Muller, Volkmar and Pantel, Klaus and Minn, Andy J. and Bissell, Mina J. and Garcia, Benjamin A. and Kang, Yibin and Rajasekhar, Vinagolu K. and Ghajar, Cyrus M. and Matei, Irina and Peinado, Hector and Bromberg, Jacqueline and Lyden, David},
abstractNote = {Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. In this paper, 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. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.},
doi = {10.1038/nature15756},
journal = {Nature (London)},
number = 7578,
volume = 527,
place = {United States},
year = {2015},
month = {10}
}

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    Replication study: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET
    journal, December 2018


    Tumor‐derived exosomes (TDEs): How to avoid the sting in the tail
    journal, May 2019

    • Wan, MeiHua; Ning, Bo; Spiegel, Sarah
    • Medicinal Research Reviews, Vol. 40, Issue 1
    • DOI: 10.1002/med.21623

    Biological functions and clinical applications of exosomal non-coding RNAs in hepatocellular carcinoma
    journal, July 2019


    Post-translational modification and protein sorting to small extracellular vesicles including exosomes by ubiquitin and UBLs
    journal, July 2019


    Exosomes, metastases, and the miracle of cancer stem cell markers
    journal, April 2019


    Exosomes as a storehouse of tissue remodeling proteases and mediators of cancer progression
    journal, September 2019

    • Das, Alakesh; Mohan, Vishnu; Krishnaswamy, Venkat Raghavan
    • Cancer and Metastasis Reviews, Vol. 38, Issue 3
    • DOI: 10.1007/s10555-019-09813-5

    Brain Theranostics and Radiotheranostics: Exosomes and Graphenes In Vivo as Novel Brain Theranostics
    journal, November 2018


    Extracellular vesicles from human urine-derived stem cells prevent osteoporosis by transferring CTHRC1 and OPG
    journal, June 2019


    Perspective: bidirectional exosomal transport between cancer stem cells and their fibroblast-rich microenvironment during metastasis formation
    journal, July 2018


    Every step of the way: integrins in cancer progression and metastasis
    journal, July 2018


    Extracellular vesicles in type 2 diabetes mellitus: key roles in pathogenesis, complications, and therapy
    journal, June 2019


    Cortactin promotes exosome secretion by controlling branched actin dynamics
    journal, July 2016

    • Sinha, Seema; Hoshino, Daisuke; Hong, Nan Hyung
    • The Journal of Cell Biology, Vol. 214, Issue 2
    • DOI: 10.1083/jcb.201601025

    Tumour–adipose tissue crosstalk: fuelling tumour metastasis by extracellular vesicles
    journal, November 2017

    • Robado de Lope, Lucía; Alcíbar, Olwen Leaman; Amor López, Ana
    • Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 373, Issue 1737
    • DOI: 10.1098/rstb.2016.0485

    Lipidomic characterization of extracellular vesicles in human serum
    journal, January 2019

    • Chen, Suming; Datta-Chaudhuri, Amrita; Deme, Pragney
    • Journal of Circulating Biomarkers, Vol. 8
    • DOI: 10.1177/1849454419879848

    Selecting short length nucleic acids localized in exosomes improves plasma EGFR mutation detection in NSCLC patients
    journal, October 2019


    Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts
    journal, December 2019


    Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma
    journal, April 2018

    • Huang, Ruixia; Rofstad, Einar K.
    • Journal of Experimental & Clinical Cancer Research, Vol. 37, Issue 1
    • DOI: 10.1186/s13046-018-0763-x

    Integrins: Moonlighting Proteins in Invadosome Formation
    journal, May 2019


    Are Integrins Still Practicable Targets for Anti-Cancer Therapy?
    journal, July 2019


    Liquid Biopsy for the Detection of Resistance Mechanisms in NSCLC: Comparison of Different Blood Biomarkers
    journal, July 2019

    • Pasini, Luigi; Ulivi, Paola
    • Journal of Clinical Medicine, Vol. 8, Issue 7
    • DOI: 10.3390/jcm8070998

    Melanoma-Derived Extracellular Vesicles: Focus on Their Proteome
    journal, May 2019


    Challenges in the Isolation and Proteomic Analysis of Cancer Exosomes—Implications for Translational Research
    journal, May 2019