LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest.
OBJECTIVE
Patients carrying germline mutations of LKB1 have an increased risk of pancreatic cancer; however, it is unclear whether down-regulation of LKB1 is an important event in sporadic pancreatic cancer. In this study, we aimed to investigate the impact of LKB1 down-regulation for pancreatic cancer in mouse and human and to elucidate the mechanism by which Lkb1 deregulation contributes to this disease.


METHODS
We first investigated the consequences of Lkb1 deficiency in a genetically modified mouse model of pancreatic cancer, both in terms of disease progression and at the molecular level. To test the relevance of our findings to human pancreatic cancer, we investigated levels of LKB1 and its potential targets in human pancreatic cancer.


RESULTS
We definitively show that Lkb1 haploinsufficiency can cooperate with oncogenic KrasG12D to cause pancreatic ductal adenocarcinoma (PDAC) in the mouse. Mechanistically, this was associated with decreased p53/p21-dependent growth arrest. Haploinsufficiency for p21 (Cdkn1a) also synergizes with KrasG12D to drive PDAC in the mouse. We also found that levels of LKB1 expression were decreased in around 20% of human PDAC and significantly correlated with low levels of p21 and a poor prognosis. Remarkably, all tumors that had low levels of LKB1 had low levels of p21, and these tumors did not express mutant p53.


CONCLUSIONS
We have identified a novel LKB1-p21 axis that suppresses PDAC following Kras mutation in vivo. Down-regulation of LKB1 may therefore serve as an alternative to p53 mutation to drive pancreatic cancer in vivo.
Morton
Jennifer P
JP
Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK.
Jamieson
Nigel B
NB
Karim
Saadia A
SA
Athineos
Dimitris
D
Ridgway
Rachel A
RA
Nixon
Colin
C
McKay
Colin J
CJ
Carter
Ross
R
Brunton
Valerie G
VG
Frame
Margaret C
MC
Ashworth
Alan
A
Oien
Karin A
KA
Evans
T R Jeffry
TR
Sansom
Owen J
OJ
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C084010:pancreatic and duodenal homeobox 1 protein; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
Cancer Res. 2005 Nov 15;65(22):10280-8
16288016
Nat Cell Biol. 2007 Sep;9(9):1016-24
17762893
Nature. 2007 Aug 16;448(7155):807-10
17676035
Mol Cell. 2009 Jan 30;33(2):237-47
19187764
Nature. 1998 Jan 8;391(6663):184-7
9428765
Cell. 1988 May 20;53(4):549-54
2453289
Mol Cell. 2001 Jun;7(6):1307-19
11430832
Biochem Biophys Res Commun. 1999 Aug 11;261(3):750-5
10441497
Cancer Cell. 2003 Dec;4(6):437-50
14706336
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
17237035
Gastroenterology. 2004 Jun;126(7):1788-94
15188174
Gut. 2006 Jul;55(7):984-90
16407375
Nat Genet. 1997 Jan;15(1):87-90
8988175
Science. 2001 Aug 17;293(5533):1323-6
11509733
Nature. 2002 Sep 12;419(6903):162-7
12226664
Development. 2002 May;129(10):2447-57
11973276
Br J Cancer. 2004 Nov 1;91(9):1633-8
15494719
EMBO J. 2005 May 18;24(10):1810-20
15889149
Cell. 1995 Aug 25;82(4):675-84
7664346
Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9248-51
10430928
Gastroenterology. 2000 Dec;119(6):1447-53
11113065
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12327-32
12218179
Neoplasia. 2003 Jul-Aug;5(4):367-74
14511408
Nature. 2005 Aug 4;436(7051):642
16079833
Am J Pathol. 1993 May;142(5):1534-43
8494051
Cancer Res. 2002 Apr 15;62(8):2261-6
11956081
Cancer Res. 2006 Nov 15;66(22):10701-8
17108107
Am J Pathol. 2001 Dec;159(6):2017-22
11733352
Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8903-8
12060709
J Am Coll Surg. 1999 Jul;189(1):1-7
10401733
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35
14985505
Hum Mol Genet. 2002 Jun 15;11(13):1497-504
12045203
Oncogene. 2000 Jan 6;19(1):164-8
10644993
PLoS One. 2009;4(1):e4264
19165340
Mol Cell Biol. 2008 Apr;28(7):2414-25
18227155
Clin Cancer Res. 2000 Aug;6(8):2969-72
10955772
Cancer Res. 2004 Mar 1;64(5):1669-74
14996726
J Clin Invest. 2003 Jan;111(1):91-8
12511592