Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells.
Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that CAFs exposed to chemotherapy have an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.|Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.
K E
KE
Richards
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.|Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.|Integrated Biomedical Sciences Program, University of Notre Dame, South Bend, IN, USA.
A E
AE
Zeleniak
Department of Pediatrics, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA.|Department of Pharmacology, Indiana University, Indianapolis, IN, USA.|Indiana University Simon Cancer Center, Indianapolis, IN, USA.|Department of Toxicology, Indiana University, Indianapolis, IN, USA.
M L
ML
Fishel
Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.|Department of Chemistry, University of Notre Dame, Notre Dame, IN, USA.|Department of Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
J
J
Wu
Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.|Integrated Biomedical Sciences Program, University of Notre Dame, South Bend, IN, USA.|Indiana University Simon Cancer Center, Indianapolis, IN, USA.|Department of Chemistry, University of Notre Dame, Notre Dame, IN, USA.|Department of Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
L E
LE
Littlepage
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.|Department of Biological Sciences, Harper Cancer Research Institute, University of Notre Dame, South Bend, IN, USA.|Integrated Biomedical Sciences Program, University of Notre Dame, South Bend, IN, USA.|Indiana University Simon Cancer Center, Indianapolis, IN, USA.
R
R
Hill
D000199:Actins / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015415:Biomarkers; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors / Q000235:genetics; D014746:Vimentin / Q000378:metabolism; D000093542:Gemcitabine
D000199:Actins; D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D017077:Culture Media, Conditioned; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D000071250:Snail Family Transcription Factors; D014746:Vimentin; D003841:Deoxycytidine; D000093542:Gemcitabine
Cell. 2012 Dec 21;151(7):1542-56
23260141
Biochim Biophys Acta. 2015 Nov;1852(11):2362-71
26300484
Cancer Cell. 2014 Apr 14;25(4):501-15
24735924
JAMA. 2007 Jan 17;297(3):267-77
17227978
Int J Cancer. 2007 Aug 15;121(4):699-705
17534898
Cell. 2014 Oct 23;159(3):499-513
25417103
Neurobiol Aging. 2014 Aug;35(8):1792-800
24650793
Int J Oncol. 2012 Dec;41(6):2093-102
23026911
Nat Cell Biol. 2007 Jun;9(6):654-9
17486113
Oncogene. 2003 May 22;22(21):3243-51
12761494
Cancer Res. 2005 Oct 1;65(19):9064-72
16204081
Anal Bioanal Chem. 2015 May;407(12):3285-301
25821114
Cancer Res. 2014 Jun 1;74(11):2913-21
24840647
Nat Cell Biol. 2014 Mar;16(3):268-80
24561623
N Engl J Med. 2013 Oct 31;369(18):1691-703
24131140
Cancer Cell. 2014 Jun 16;25(6):735-47
24856585
Nat Rev Gastroenterol Hepatol. 2015 Jul;12(7):371
26035680
Biochem Biophys Res Commun. 2014 Aug 22;451(2):295-301
25086355
Anal Biochem. 2015 Sep 1;484:58-65
25981981
J Proteomics. 2010 Sep 10;73(10):1907-20
20601276
PLoS One. 2015 May 04;10 (5):e0125625
25938772
Cell Death Differ. 2015 Jan;22(1):34-45
25236394
Oncogene. 2013 May 30;32(22):2747-55
22797057
J Cell Biochem. 2007 Jul 1;101(4):887-907
17266048
Cancer Res. 2009 Jul 1;69(13):5575-83
19549912
Cancer Res. 2009 Jul 15;69(14 ):5820-8
19584296
Int Immunol. 2005 Jul;17(7):879-87
15908444
Nat Rev Clin Oncol. 2010 Mar;7(3):163-72
20101258
J Biol Chem. 2013 Jun 14;288(24):17713-24
23653359
Oncogene. 2014 Feb 13;33(7):899-908
23416978
J Biol Chem. 2013 Jul 19;288(29):21197-207
23740244
Science. 2009 Jun 12;324(5933):1457-61
19460966
Mol Cancer Ther. 2016 May;15(5):1043-52
26939701
Nature. 2015 Nov 5;527(7576):100-4
26479035
Cell Death Dis. 2015 Jun 25;6:e1795
26111057
J Exp Clin Cancer Res. 2014 Aug 02;33:62
25084828
Cancer Res. 2008 Feb 1;68(3):918-26
18245495
PLoS One. 2013 Aug 22;8(8):e71978
23991015
J Extracell Vesicles. 2014 Mar 26;3:null
24683445
Nature. 2015 Nov 19;527(7578):329-35
26524530