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; 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 K. Batra; William R. Jarnagin; Robert E. Schwartz; Irina Matei; Héctor Peinado; Ben Z. Stanger; Jacqueline Bromberg; David Lyden

doi:10.1038/ncb3169

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 LaboriInger Marie Bowitz Lothe, Elin H. Kure, Jonathan Hernandez, Alexandre Doussot, Saya H. Ebbesen, Paul M. Grandgenett, Michael A. Hollingsworth, Maneesh Jain, Kavita Mallya, Surinder K. Batra, William R. Jarnagin, Robert E. Schwartz, Irina Matei, Héctor Peinado, Ben Z. Stanger, Jacqueline Bromberg, David Lyden

Research output: Contribution to journal › Article › peer-review

2029 Scopus citations

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 language	English (US)
Pages (from-to)	816-826
Number of pages	11
Journal	Nature Cell Biology
Volume	17
Issue number	6
DOIs	https://doi.org/10.1038/ncb3169
State	Published - Jun 1 2015

ASJC Scopus subject areas

Cell Biology

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Costa-Silva, B., Aiello, N. M., Ocean, A. J., Singh, S., Zhang, H., Thakur, B. K., Becker, A., Hoshino, A., Mark, M. T., Molina, H., Xiang, J., Zhang, T., Theilen, T. M., García-Santos, G., Williams, C., Ararso, Y., Huang, Y., Rodrigues, G., Shen, T. L., ... 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

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

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title = "Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver",

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.",

author = "Bruno Costa-Silva and Aiello, {Nicole M.} and Ocean, {Allyson J.} and Swarnima Singh and Haiying Zhang and Thakur, {Basant Kumar} and Annette Becker and Ayuko Hoshino and Mark, {Milica Te{\v s}i{\'c}} and Henrik Molina and Jenny Xiang and Tuo Zhang and Theilen, {Till Martin} and Guillermo Garc{\'i}a-Santos and Caitlin Williams and Yonathan Ararso and Yujie Huang and Gon{\c c}alo Rodrigues and Shen, {Tang Long} and Labori, {Knut J{\o}rgen} and Lothe, {Inger Marie Bowitz} and Kure, {Elin H.} and Jonathan Hernandez and Alexandre Doussot and Ebbesen, {Saya H.} and Grandgenett, {Paul M.} and Hollingsworth, {Michael A.} and Maneesh Jain and Kavita Mallya and Batra, {Surinder K.} and Jarnagin, {William R.} and Schwartz, {Robert E.} and Irina Matei and H{\'e}ctor Peinado and Stanger, {Ben Z.} and Jacqueline Bromberg and David Lyden",

year = "2015",

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doi = "10.1038/ncb3169",

language = "English (US)",

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T1 - Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

AU - Costa-Silva, Bruno

AU - Aiello, Nicole M.

AU - Ocean, Allyson J.

AU - Singh, Swarnima

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 K.

AU - Jarnagin, William R.

AU - Schwartz, Robert E.

AU - Matei, Irina

AU - Peinado, Héctor

AU - Stanger, Ben Z.

AU - Bromberg, Jacqueline

AU - Lyden, David

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

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JO - Nature Cell Biology

JF - Nature Cell Biology

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ER -

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

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