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Title: Tumour exosome integrins determine organotropic metastasis

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:
Grant/Contract Number:
AC02-05CH11231; P30 CA008748; U01-CA169538; R01-CA169416; W81XWH-13-10249; W81XWH-13-1-0425; 101-2918-I-002-016
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
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)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; metastasis; cancer microenvironment; mechanisms of disease
OSTI Identifier:
1378654

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., 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. 2015. "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}
}