Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Bruno Costa-Silva, Nicole M. Aiello, Allyson J. Ocean, Swarnima Singh, Haiying Zhang, Basant Kumar Thakur, Annette Becker, Ayuko Hoshino, Milica Tešić Mark, Henrik Molina, Jenny Xiang, Tuo Zhang, Till Martin Theilen, Guillermo García-Santos, Caitlin Williams, Yonathan Ararso, Yujie Huang, Gonçalo Rodrigues, Tang Long Shen, Knut Jørgen Labori & 17 others Inger Marie Bowitz Lothe, Elin H. Kure, Jonathan Hernandez, Alexandre Doussot, Saya H. Ebbesen, Paul M. Grandgenett, Michael A Hollingsworth, Maneesh Jain, Kavita Mallya, Surinder Kumar Batra, William R. Jarnagin, Robert E. Schwartz, Irina Matei, Héctor Peinado, Ben Z. Stanger, Jacqueline Bromberg, David Lyden

Research output: Contribution to journalArticle

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Abstract

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

Original languageEnglish (US)
Pages (from-to)816-826
Number of pages11
JournalNature Cell Biology
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2015

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Exosomes
Pancreatic Neoplasms
Adenocarcinoma
Liver
Neoplasm Metastasis
Macrophage Migration-Inhibitory Factors
Hepatic Stellate Cells
Kupffer Cells
Transforming Growth Factors
Fibronectins
Up-Regulation
Macrophages
Neoplasms

ASJC Scopus subject areas

  • Cell Biology

Cite this

Costa-Silva, B., Aiello, N. M., Ocean, A. J., Singh, S., Zhang, H., Thakur, B. K., ... Lyden, D. (2015). Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biology, 17(6), 816-826. https://doi.org/10.1038/ncb3169

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. / Costa-Silva, Bruno; Aiello, Nicole M.; Ocean, Allyson J.; Singh, Swarnima; Zhang, Haiying; Thakur, Basant Kumar; Becker, Annette; Hoshino, Ayuko; Mark, Milica Tešić; Molina, Henrik; Xiang, Jenny; Zhang, Tuo; Theilen, Till Martin; García-Santos, Guillermo; Williams, Caitlin; Ararso, Yonathan; Huang, Yujie; Rodrigues, Gonçalo; Shen, Tang Long; Labori, Knut Jørgen; Lothe, Inger Marie Bowitz; Kure, Elin H.; Hernandez, Jonathan; Doussot, Alexandre; Ebbesen, Saya H.; Grandgenett, Paul M.; Hollingsworth, Michael A; Jain, Maneesh; Mallya, Kavita; Batra, Surinder Kumar; Jarnagin, William R.; Schwartz, Robert E.; Matei, Irina; Peinado, Héctor; Stanger, Ben Z.; Bromberg, Jacqueline; Lyden, David.

In: Nature Cell Biology, Vol. 17, No. 6, 01.06.2015, p. 816-826.

Research output: Contribution to journalArticle

Costa-Silva, B, Aiello, NM, Ocean, AJ, Singh, S, Zhang, H, Thakur, BK, Becker, A, Hoshino, A, Mark, MT, Molina, H, Xiang, J, Zhang, T, Theilen, TM, García-Santos, G, Williams, C, Ararso, Y, Huang, Y, Rodrigues, G, Shen, TL, Labori, KJ, Lothe, IMB, Kure, EH, Hernandez, J, Doussot, A, Ebbesen, SH, Grandgenett, PM, Hollingsworth, MA, Jain, M, Mallya, K, Batra, SK, Jarnagin, WR, Schwartz, RE, Matei, I, Peinado, H, Stanger, BZ, Bromberg, J & Lyden, D 2015, 'Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver', Nature Cell Biology, vol. 17, no. 6, pp. 816-826. https://doi.org/10.1038/ncb3169
Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biology. 2015 Jun 1;17(6):816-826. https://doi.org/10.1038/ncb3169
Costa-Silva, Bruno ; Aiello, Nicole M. ; Ocean, Allyson J. ; Singh, Swarnima ; Zhang, Haiying ; Thakur, Basant Kumar ; Becker, Annette ; Hoshino, Ayuko ; Mark, Milica Tešić ; Molina, Henrik ; Xiang, Jenny ; Zhang, Tuo ; Theilen, Till Martin ; García-Santos, Guillermo ; Williams, Caitlin ; Ararso, Yonathan ; Huang, Yujie ; Rodrigues, Gonçalo ; Shen, Tang Long ; Labori, Knut Jørgen ; Lothe, Inger Marie Bowitz ; Kure, Elin H. ; Hernandez, Jonathan ; Doussot, Alexandre ; Ebbesen, Saya H. ; Grandgenett, Paul M. ; Hollingsworth, Michael A ; Jain, Maneesh ; Mallya, Kavita ; Batra, Surinder Kumar ; Jarnagin, William R. ; Schwartz, Robert E. ; Matei, Irina ; Peinado, Héctor ; Stanger, Ben Z. ; Bromberg, Jacqueline ; Lyden, David. / Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. In: Nature Cell Biology. 2015 ; Vol. 17, No. 6. pp. 816-826.
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AU - Zhang, Haiying

AU - Thakur, Basant Kumar

AU - Becker, Annette

AU - Hoshino, Ayuko

AU - Mark, Milica Tešić

AU - Molina, Henrik

AU - Xiang, Jenny

AU - Zhang, Tuo

AU - Theilen, Till Martin

AU - García-Santos, Guillermo

AU - Williams, Caitlin

AU - Ararso, Yonathan

AU - Huang, Yujie

AU - Rodrigues, Gonçalo

AU - Shen, Tang Long

AU - Labori, Knut Jørgen

AU - Lothe, Inger Marie Bowitz

AU - Kure, Elin H.

AU - Hernandez, Jonathan

AU - Doussot, Alexandre

AU - Ebbesen, Saya H.

AU - Grandgenett, Paul M.

AU - Hollingsworth, Michael A

AU - Jain, Maneesh

AU - Mallya, Kavita

AU - Batra, Surinder Kumar

AU - Jarnagin, William R.

AU - Schwartz, Robert E.

AU - Matei, Irina

AU - Peinado, Héctor

AU - Stanger, Ben Z.

AU - Bromberg, Jacqueline

AU - Lyden, David

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