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

TitlePancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.
Publication TypeJournal Article
Year of Publication2015
AuthorsCosta-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BKumar, Becker A, Hoshino A, Mark MTešić, Molina H, Xiang J, Zhang T, Theilen T-M, García-Santos G, Williams C, Ararso Y, Huang Y, Rodrigues G, Shen T-L, Labori KJørgen, Lothe IMarie Bowi, Kure EH, Hernandez JM, 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 JF, Lyden DC
JournalNat Cell Biol
Date Published2015 Jun
KeywordsAnimals, Base Sequence, Bone Marrow Cells, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Movement, Exosomes, Female, Fibronectins, Gene Expression Regulation, Neoplastic, Hepatic Stellate Cells, Humans, Liver, Liver Neoplasms, Macrophage Migration-Inhibitory Factors, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Pancreatic Neoplasms, Precancerous Conditions, RNA Interference, RNA, Small Interfering, Sequence Analysis, RNA, Signal Transduction, Transforming Growth Factor beta

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.

Custom 1

Alternate JournalNat. Cell Biol.
PubMed ID25985394
PubMed Central IDPMC5769922
Grant ListU54 CA163120 / CA / NCI NIH HHS / United States
U01 CA111294 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P50 CA127297 / CA / NCI NIH HHS / United States
R50 CA211462 / CA / NCI NIH HHS / United States

Weill Cornell Medicine Gale and Ira Drukier Institute for Children's Health 413 E. 69th Street New York, NY 10021