TY - JOUR
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
N1 - Funding Information:
We thank D. L. Bajor (Vonderheide laboratory, University of Pennsylvania) for the gift of the R6560B cells. We thank L. Bojmar for carefully reviewing the paper. We thank S. Rudchenko and M. Barbu-Stevanovic at the Hospital for Special Surgery Fannie E. Rippel Foundation Flow Cytometry Core Facility for expert flow cytometry. We are supported by grants from the Children’s Cancer and Blood Foundation (H.P., D.L.), Manning Foundation (D.L.), Hartwell Foundation (D.L.), Champalimaud Foundation (D.L.), Fundacao para a Ciencia e a Tecnologia (D.L.), Nancy C and Daniel P Paduano Foundation (H.P., D.L.), Mary Kay Foundation (D.L.), Pediatric Oncology Experimental Therapeutic Investigator Consortium (D.L.), James Paduano Foundation (D.L., H.P.), Melanoma Research Alliance (H.P.), Sohn Conference Foundation (H.P.), Beth Tortolani Foundation (D.L., J.B.), Malcolm Hewitt Weiner Foundation (D.L.), Jose Carreras Leukemia Foundation (B.K.T.), Theodore Rapp Foundation (D.L.), American Hellenic Educational Progressive Association 5th District Cancer Research Foundation (D.L.), Charles and Marjorie Holloway Foundation (J.B.), Sussman Family Fund (J.B.), Lerner Foundation (J.B.), Breast Cancer Alliance (J.B.), and Manhasset Women’s Coalition Against Breast Cancer (J.B.).
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
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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U2 - 10.1038/ncb3169
DO - 10.1038/ncb3169
M3 - Article
C2 - 25985394
AN - SCOPUS:84930170395
SN - 1465-7392
VL - 17
SP - 816
EP - 826
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 6
ER -