Oncogenic Ras/Src cooperativity in pancreatic neoplasia.
Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5-8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA's indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer.
Department of Pathology, Moore's UCSD Cancer Center, San Diego, CA, USA.
D J
DJ
Shields
E A
EA
Murphy
J S
JS
Desgrosellier
A
A
Mielgo
S K M
SK
Lau
L A
LA
Barnes
J
J
Lesperance
M
M
Huang
C
C
Schmedt
D
D
Tarin
A M
AM
Lowy
D A
DA
Cheresh
D000818:Animals; D045744:Cell Line, Tumor; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018631:ras Proteins / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology*
D019061:src-Family Kinases; D018631:ras Proteins
Am J Pathol. 2006 Mar;168(3):962-72
16507911
Oncogene. 2000 Jun 1;19(24):2867-9
10851090
Mol Cell. 1999 Dec;4(6):915-24
10635317
Genes Dev. 2006 Nov 15;20(22):3130-46
17114584
Genes Dev. 2001 Dec 15;15(24):3243-8
11751630
Cancer Cell. 2003 Dec;4(6):437-50
14706336
Carcinogenesis. 2008 Oct;29(10):1862-8
18544561
Oncogene. 2000 Nov 20;19(49):5636-42
11114744
Am J Pathol. 2000 Jun;156(6):1821-5
10854204
Oncogene. 2004 Oct 18;23(48):7957-68
15489913
Cancer Res. 2009 Feb 15;69(4):1383-91
19208836
Clin Cancer Res. 2004 Dec 1;10(23):8028-36
15585638
Proc Natl Acad Sci U S A. 1980 Mar;77(3):1311-5
6246487
J Pathol. 1990 Jul;161(3):195-200
2202801
Nature. 1992 Oct 8;359(6395):554-6
1406976
Mutat Res. 2000 Nov 20;455(1-2):81-95
11113469
Nature. 1976 Mar 11;260(5547):170-3
176594
Am J Surg Pathol. 2004 Aug;28(8):977-87
15252303
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
Int J Gastrointest Cancer. 2006;37(4):110-9
18175225
Cancer Cell. 2005 May;7(5):469-83
15894267
Pancreatology. 2008;8(4-5):462-9
18724072
J Pathol. 1991 Feb;163(2):111-6
1707959
Int J Cancer. 2008 Jun 15;122(12):2665-73
18351644
Br J Cancer. 2009 Jul 21;101(2):263-8
19603032
Dev Cell. 2006 Jan;10(1):33-44
16399076
Nat Rev Mol Cell Biol. 2001 Jun;2(6):467-75
11389470
J Biol Chem. 2007 Feb 23;282(8):5327-39
17189253
Biochem Biophys Res Commun. 1998 Feb 13;243(2):503-8
9480838
Cancer Cell. 2007 Mar;11(3):229-43
17349581
J Pharmacol Exp Ther. 2006 Jul;318(1):161-72
16627750
Nat Med. 2009 Oct;15(10):1163-9
19734908
Cancer Cell. 2004 Sep;6(3):209-14
15380511
Nature. 1998 Aug 27;394(6696):901-4
9732874
Gut. 2008 Nov;57(11):1555-60
18664506
Cancer Res. 2007 Jul 1;67(13):6075-82
17616662
Genes Dev. 2006 May 15;20(10):1218-49
16702400
J Clin Invest. 1993 Jan;91(1):53-60
7678609
Genes Dev. 2006 Nov 15;20(22):3147-60
17114585
Cell. 1988 May 20;53(4):549-54
2453289
Brain Pathol. 1999 Oct;9(4):627-37
10517501
Genes Dev. 2003 Dec 15;17(24):3112-26
14681207
Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5242-7
18356293
J Exp Med. 1911 Apr 1;13(4):397-411
19867421
Int J Cancer. 2009 Dec 1;125(11):2547-55
19623650
Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9343-8
18607000
J Med Chem. 2004 Dec 30;47(27):6658-61
15615512
Gastroenterology. 2010 Jul;139(1):292-303
20303350
Mol Carcinog. 2004 Aug;40(4):189-200
15264211
N Engl J Med. 1992 Feb 13;326(7):455-65
1732772
Int J Cancer. 2003 Sep 20;106(5):806-11
12866043