Molecular signatures of mu opioid receptor and somatostatin receptor 2 in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy, has been linked to atypical levels, certain mutations, and aberrant signaling of G-protein-coupled receptors (GPCRs). GPCRs have been challenging to target in cancer because they organize into complex networks in tumor cells. To dissect such networks with nanometer-scale precision, here we combine traditional biochemical approaches with superresolution microscopy methods. A novel interaction specific to PDAC is identified between mu opioid receptor (MOR) and somatostatin receptor 2 (SSTR2). Although MOR and SSTR2 did not colocalize in healthy pancreatic cells or matching healthy patient tissues, the pair did significantly colocalize in pancreatic cancer cells, multicellular tumor spheroids, and cancerous patient tissues. Moreover, this association in pancreatic cancer cells correlated with functional cross-talk and increased metastatic potential of cells. Coactivation of MOR and SSTR2 in PDAC cells led to increased expression of mesenchymal markers and decreased expression of an epithelial marker. Together these results suggest that the MOR-SSTR2 heteromer may constitute a novel therapeutic target for PDAC.
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Raphael
R
Jorand
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Sunetra
S
Biswas
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Devin L
DL
Wakefield
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Steven J
SJ
Tobin
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Ottavia
O
Golfetto
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Kelsey
K
Hilton
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Michelle
M
Ko
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813.
Joe W
JW
Ramos
Department of Physics and Astronomy, California State Polytechnic University, Pomona, CA 91768.
Alexander R
AR
Small
Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Peiguo
P
Chu
Division of Surgical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010.
Gagandeep
G
Singh
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010 ttalisman@coh.org.
Tijana
T
Jovanovic-Talisman
D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D010190:Pancreatic Neoplasms / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
D017450:Receptors, Opioid, mu; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2
Br J Cancer. 2011 Apr 12;104(8):1296-302
21448168
J Biol Chem. 2012 May 11;287(20):16768-80
22442147
Mol Pharmacol. 2003 Dec;64(6):1391-401
14645669
Medchemcomm. 2013 May 1;4(5):847-851
23682308
J Biol Chem. 2015 Feb 13;290(7):3875-92
25516594
Cell. 1995 Jan 27;80(2):179-85
7834738
Growth Factors. 2006 Mar;24(1):21-44
16393692
Int J Cancer. 2007 Aug 15;121(4):699-705
17534898
Nat Neurosci. 2015 Jan;18(1):75-86
25485758
Sci Rep. 2016 Feb 17;6:21648
26884312
Nat Methods. 2008 Nov;5(11):943-5
18794861
Nat Methods. 2010 Sep;7(9):717-9
20693998
Prog Mol Biol Transl Sci. 2013;117:207-65
23663971
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7682-7
17452637
Cancer Cell Int. 2013 Sep 23;13(1):93
24059654
J Biol Chem. 2006 Jan 13;281(2):1261-73
16280323
Clin Cancer Res. 2000 Sep;6(9):3530-5
10999740
Oncogene. 2001 Mar 26;20(13):1563-9
11313903
World J Surg Oncol. 2015 Feb 13;13:46
25890201
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17456-61
24101516
EMBO J. 2011 May 03;30(12):2350-63
21540834
Nat Med. 2001 Sep;7(9):1003-9
11533702
Nature. 2010 Aug 12;466(7308):869-73
20668451
J Cell Biol. 2004 Mar 1;164(5):689-99
14981092
Mol Pharmacol. 2005 Jun;67(6):2173-84
15778451
Int J Cancer. 1975 May 15;15(5):741-7
1140870
Nat Commun. 2015 Jun 12;6:7347
26066572
N Engl J Med. 2013 Oct 31;369(18):1691-703
24131140
J Biotechnol. 2010 Jul 1;148(1):3-15
20097238
J Biol Chem. 2006 Apr 21;281(16):10856-64
16492667
FASEB J. 2007 Aug;21(10 ):2455-65
17384143
Nat Chem Biol. 2010 Aug;6(8):587-94
20622858
Lancet. 2004 Mar 27;363(9414):1049-57
15051286
Cell. 2011 Mar 4;144(5):646-74
21376230
Eur J Endocrinol. 2005 Jul;153(1):135-41
15994755
Cancer Res. 2009 Mar 15;69(6):2400-7
19276344
Sci Signal. 2010 Jul 20;3(131):ra54
20647592
Br J Anaesth. 2014 Jul;113 Suppl 1:i103-8
24920011
Nat Biotechnol. 2014 Feb;32(2):191-8
24463572
J Biol Chem. 2014 Aug 8;289(32):21960-72
24942731
PLoS One. 2012;7(12):e49789
23272051
Mol Endocrinol. 2008 Oct;22(10 ):2278-92
18653781
Ann Surg Oncol. 2007 Dec;14(12):3527-33
17879119
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5135-9
15044695
Anesth Analg. 2011 Dec;113(6):1353-64
22003224
Oncogene. 2014 Jun 26;33(26):3401-10
23912455
Neuropharmacology. 2011 Sep;61(4):770-7
21645528
J Biol Chem. 2002 May 31;277(22):19762-72
11896051
Biophys J. 2006 Dec 1;91(11):4258-72
16980368
Cancer. 2013 Dec 1;119(23):4103-10
24104703
PLoS One. 2014 Feb 04;9(2):e87225
24503624
J Biol Chem. 2004 Aug 20;279(34):35518-25
15205453
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17769-74
19805200
Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4125-33
15217949
Neuropsychopharmacology. 2009 Mar;34(4):972-86
18800071
J Biomed Opt. 2014 Jan;19(1):011021
24297043
Int J Gastrointest Cancer. 2006;37(4):110-9
18175225
Cancer Res. 2009 Jul 15;69(14 ):5820-8
19584296
J Biol Chem. 2001 Sep 7;276(36):33847-53
11457825
Nat Methods. 2006 Oct;3(10):793-5
16896339
Annu Rev Pharmacol Toxicol. 2016;56:403-25
26514203
Oncol Rep. 2012 May;27(5):1599-605
22322379
J Biol Chem. 2009 Sep 25;284(39):26732-41
19542234
Sci Rep. 2014 Aug 01;4:5911
25081383
Nat Methods. 2011 Sep 18;8(11):969-75
21926998
J Pharmacol Exp Ther. 2011 Feb;336(2):296-302
21030484
Science. 1988 Apr 8;240(4849):177-84
2451290
Science. 1999 Nov 12;286(5443):1358-62
10558990
Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19208-13
16365317
Clin Cancer Res. 2004 Apr 15;10(8):2832-45
15102692
J Surg Res. 2004 Jun 15;119(2):130-7
15145694
Clin J Pain. 2010 Nov-Dec;26(9):794-7
20973155
Mol Pharmacol. 2012 Feb;81(2):264-72
22072818
Cancer. 1990 May 15;65(10):2279-90
1971771
J Neuroimmunol. 2008 Jul 15;197(2):114-23
18533278
Am J Physiol Endocrinol Metab. 2012 Nov 1;303(9):E1107-16
22932785
Cold Spring Harb Perspect Biol. 2009 Dec;1(6):a003129
20457567
Br J Cancer. 1995 Jan;71(1):97-101
7819058
Nat Methods. 2011 Nov 06;8(12):1027-36
22056676
Eur J Immunol. 2008 Feb;38(2):537-49
18200497
Nat Rev Cancer. 2004 Jul;4(7):540-50
15229479
BMC Cancer. 2008 Feb 06;8:43
18254976
J Clin Oncol. 2007 May 20;25(15):1960-6
17452677
Circ Res. 2010 Jan 8;106(1):79-88
19926878
Cell. 1982 Nov;31(1):11-24
6186379
Therap Adv Gastroenterol. 2013 Jul;6(4):321-37
23814611
J Clin Invest. 1992 Oct;90(4):1352-60
1401070
Biochim Biophys Acta. 2015 Jan;1855(1):43-9
25432020
Pharmacol Ther. 2009 Mar;121(3):285-93
19100766
Gen Pharmacol. 1996 Oct;27(7):1099-107
8981054
Nat Protoc. 2013 Feb;8(2):345-54
23348362
Science. 2006 Sep 15;313(5793):1642-5
16902090
Nat Methods. 2015 Nov;12(11):1065-71
26344046
Br J Cancer. 2010 Nov 23;103(11):1671-9
21045835
Curr Opin Genet Dev. 2008 Feb;18(1):3-10
18325755
Gut. 1998 Apr;42(4):546-50
9616318
Nat Chem Biol. 2009 Mar;5(3):131-4
19219011