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 ZhangHaiying 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, Sukwinder Kaur, Maneesh Jain, Kavita Mallya, Surinder Kumar 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, David Lyden

Research output: Contribution to journalArticle

1200 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)329-335
Number of pages7
JournalNature
Volume527
Issue number7578
DOIs
StatePublished - Nov 19 2015

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Exosomes
Integrins
Neoplasm Metastasis
Lung
Neoplasms
Liver
Kupffer Cells
Brain Neoplasms
Proteomics
Endothelial Cells
Fibroblasts
Epithelial Cells
Phosphorylation
Gene Expression
Bone and Bones
Brain

ASJC Scopus subject areas

  • General

Cite this

Hoshino, A., Costa-Silva, B., Shen, T. L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., ... Lyden, D. (2015). Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578), 329-335. https://doi.org/10.1038/nature15756

Tumour exosome integrins determine organotropic metastasis. / 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, Sukwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder Kumar; 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.

In: Nature, Vol. 527, No. 7578, 19.11.2015, p. 329-335.

Research output: Contribution to journalArticle

Hoshino, A, Costa-Silva, B, Shen, TL, Rodrigues, G, Hashimoto, A, Tesic Mark, M, Molina, H, Kohsaka, S, Di Giannatale, A, Ceder, S, Singh, S, Williams, C, Soplop, N, Uryu, K, Pharmer, L, King, T, Bojmar, L, Davies, AE, Ararso, Y, Zhang, T, Zhang, H, Hernandez, J, Weiss, JM, Dumont-Cole, VD, Kramer, K, Wexler, LH, Narendran, A, Schwartz, GK, Healey, JH, Sandstrom, P, Jørgen Labori, K, Kure, EH, Grandgenett, PM, Hollingsworth, MA, De Sousa, M, Kaur, S, Jain, M, Mallya, K, Batra, SK, Jarnagin, WR, Brady, MS, Fodstad, O, Muller, V, Pantel, K, Minn, AJ, Bissell, MJ, Garcia, BA, Kang, Y, Rajasekhar, VK, Ghajar, CM, Matei, I, Peinado, H, Bromberg, J & Lyden, D 2015, 'Tumour exosome integrins determine organotropic metastasis', Nature, vol. 527, no. 7578, pp. 329-335. https://doi.org/10.1038/nature15756
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015 Nov 19;527(7578):329-335. https://doi.org/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, Sukwinder ; Jain, Maneesh ; Mallya, Kavita ; Batra, Surinder Kumar ; 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. In: Nature. 2015 ; Vol. 527, No. 7578. pp. 329-335.
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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.",
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AU - Tesic Mark, Milica

AU - Molina, Henrik

AU - Kohsaka, Shinji

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AU - Wexler, Leonard H.

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AU - Hollingsworth, Michael A

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