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

被引:2090
作者
Costa-Silva, Bruno [1 ,2 ]
Aiello, Nicole M. [3 ]
Ocean, Allyson J. [4 ]
Singh, Swarnima [1 ,2 ]
Zhang, Haiying [1 ,2 ]
Thakur, Basant Kumar [1 ,2 ,5 ]
Becker, Annette [1 ,2 ]
Hoshino, Ayuko [1 ,2 ]
Mark, Milica Tesic [6 ]
Molina, Henrik [6 ]
Xiang, Jenny [7 ]
Zhang, Tuo [7 ]
Theilen, Till-Martin [1 ,2 ]
Garcia-Santos, Guillermo [1 ,2 ]
Williams, Caitlin [1 ,2 ]
Ararso, Yonathan [1 ,2 ]
Huang, Yujie [1 ,2 ]
Rodrigues, Goncalo [1 ,2 ,8 ]
Shen, Tang-Long [9 ]
Labori, Knut Jorgen [10 ]
Lothe, Inger Marie Bowitz [11 ,12 ]
Kure, Elm H. [12 ]
Hernandez, Jonathan [13 ]
Doussot, Alexandre [13 ]
Ebbesen, Saya H. [1 ,2 ]
Grandgenett, Paul M. [14 ]
Hollingsworth, Michael A. [14 ]
Jain, Maneesh [15 ]
Mallya, Kavita [15 ]
Batra, Surinder K. [15 ]
Jarnagin, William R. [13 ]
Schwartz, Robert E. [16 ]
Matei, Irina [1 ,2 ]
Peinado, Hector [1 ,2 ,17 ]
Stanger, Ben Z. [3 ]
Bromberg, Jacqueline [18 ,19 ]
Lyden, David [1 ,2 ,20 ]
机构
[1] Weill Cornell Med Coll, Meyer Canc Ctr, Childrens Canc & Blood Fdn Labs, Drukier Inst Childrens Hlth,Dept Pediat, New York, NY 10021 USA
[2] Weill Cornell Med Coll, Meyer Canc Ctr, Childrens Canc & Blood Fdn Labs, Drukier Inst Childrens Hlth,Dept Cell & Dev Biol, New York, NY 10021 USA
[3] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Gastroenterol Div,Dept Med, Philadelphia, PA 19104 USA
[4] Weill Cornell Med Coll, New York Presbyterian Hosp, Div Hematol & Med Oncol, Dept Med, New York, NY 10021 USA
[5] Hannover Med Sch, Dept Pediat Hematol & Oncol, D-30625 Hannover, Germany
[6] Rockefeller Univ, Prote Resource Ctr, New York, NY 10065 USA
[7] Weill Cornell Med Coll, Genom Resources Core Facil, New York, NY 10021 USA
[8] Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4099003 Oporto, Portugal
[9] Natl Taiwan Univ, Dept Plant Pathol & Microbiol, Taipei 10617, Taiwan
[10] Oslo Univ Hosp, Dept Hepatopancreatobiliary Surg, N-0424 Oslo, Norway
[11] Oslo Univ Hosp, Dept Pathol, N-0424 Oslo, Norway
[12] Oslo Univ Hosp, Dept Genet, Inst Canc Res, N-0424 Oslo, Norway
[13] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA
[14] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
[15] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA
[16] Weill Cornell Med Coll, Dept Med, Div Gastroenterol & Hepatol, New York, NY 10021 USA
[17] Spanish Natl Canc Res Ctr CNIO, Dept Mol Oncol, Microenvironm & Metaslasis Lab, Madrid 28029, Spain
[18] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA
[19] Weill Cornell Med Coll, New York, NY 10065 USA
[20] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA
关键词
GROWTH-FACTOR-BETA; INHIBITORY FACTOR EXPRESSION; TGF-BETA; MESENCHYMAL TRANSITION; EXTRACELLULAR VESICLES; DUCTAL ADENOCARCINOMA; KUPFFER CELLS; MOUSE MODEL; MACROPHAGES; ACTIVATION;
D O I
10.1038/ncb3169
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 beta 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.
引用
收藏
页码:816 / +
页数:20
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