LKB1 modulates lung cancer differentiation and metastasis

Hongbin Ji, Matthew R. Ramsey, D. Neil Hayes, Cheng Fan, Kate McNamara, Piotr Kozlowski, Chad Torrice, Michael C. Wu, Takeshi Shimamura, Samanthi A. Perera, Mei Chih Liang, Dongpo Cai, George N. Naumov, Lei Bao, Cristina M. Contreras, Danan Li, Liang Chen, Janakiraman Krishnamurthy, Jussi Koivunen, Lucian R. ChirieacRobert F. Padera, Roderick T. Bronson, Neal I. Lindeman, David C. Christiani, Xihong Lin, Geoffrey I. Shapiro, Pasi A. Jänne, Bruce E. Johnson, Matthew Meyerson, David J. Kwiatkowski, Diego H. Castrillon, Nabeel Bardeesy, Norman E. Sharpless, Kwok Kin Wong

Research output: Contribution to journalArticle

619 Citations (Scopus)

Abstract

Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.

Original languageEnglish (US)
Pages (from-to)807-810
Number of pages4
JournalNature
Volume448
Issue number7155
DOIs
StatePublished - Aug 16 2007

Fingerprint

Lung Neoplasms
Neoplasm Metastasis
Neoplasms
Lung
Squamous Cell Carcinoma
Carcinogenesis
Peutz-Jeghers Syndrome
Large Cell Carcinoma
Cell Line
Mutation
Hamartoma
Germ-Line Mutation
Protein-Serine-Threonine Kinases
Incidence
Genes
Adenocarcinoma of lung

ASJC Scopus subject areas

  • General

Cite this

Ji, H., Ramsey, M. R., Hayes, D. N., Fan, C., McNamara, K., Kozlowski, P., ... Wong, K. K. (2007). LKB1 modulates lung cancer differentiation and metastasis. Nature, 448(7155), 807-810. https://doi.org/10.1038/nature06030

LKB1 modulates lung cancer differentiation and metastasis. / Ji, Hongbin; Ramsey, Matthew R.; Hayes, D. Neil; Fan, Cheng; McNamara, Kate; Kozlowski, Piotr; Torrice, Chad; Wu, Michael C.; Shimamura, Takeshi; Perera, Samanthi A.; Liang, Mei Chih; Cai, Dongpo; Naumov, George N.; Bao, Lei; Contreras, Cristina M.; Li, Danan; Chen, Liang; Krishnamurthy, Janakiraman; Koivunen, Jussi; Chirieac, Lucian R.; Padera, Robert F.; Bronson, Roderick T.; Lindeman, Neal I.; Christiani, David C.; Lin, Xihong; Shapiro, Geoffrey I.; Jänne, Pasi A.; Johnson, Bruce E.; Meyerson, Matthew; Kwiatkowski, David J.; Castrillon, Diego H.; Bardeesy, Nabeel; Sharpless, Norman E.; Wong, Kwok Kin.

In: Nature, Vol. 448, No. 7155, 16.08.2007, p. 807-810.

Research output: Contribution to journalArticle

Ji, H, Ramsey, MR, Hayes, DN, Fan, C, McNamara, K, Kozlowski, P, Torrice, C, Wu, MC, Shimamura, T, Perera, SA, Liang, MC, Cai, D, Naumov, GN, Bao, L, Contreras, CM, Li, D, Chen, L, Krishnamurthy, J, Koivunen, J, Chirieac, LR, Padera, RF, Bronson, RT, Lindeman, NI, Christiani, DC, Lin, X, Shapiro, GI, Jänne, PA, Johnson, BE, Meyerson, M, Kwiatkowski, DJ, Castrillon, DH, Bardeesy, N, Sharpless, NE & Wong, KK 2007, 'LKB1 modulates lung cancer differentiation and metastasis', Nature, vol. 448, no. 7155, pp. 807-810. https://doi.org/10.1038/nature06030
Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P et al. LKB1 modulates lung cancer differentiation and metastasis. Nature. 2007 Aug 16;448(7155):807-810. https://doi.org/10.1038/nature06030
Ji, Hongbin ; Ramsey, Matthew R. ; Hayes, D. Neil ; Fan, Cheng ; McNamara, Kate ; Kozlowski, Piotr ; Torrice, Chad ; Wu, Michael C. ; Shimamura, Takeshi ; Perera, Samanthi A. ; Liang, Mei Chih ; Cai, Dongpo ; Naumov, George N. ; Bao, Lei ; Contreras, Cristina M. ; Li, Danan ; Chen, Liang ; Krishnamurthy, Janakiraman ; Koivunen, Jussi ; Chirieac, Lucian R. ; Padera, Robert F. ; Bronson, Roderick T. ; Lindeman, Neal I. ; Christiani, David C. ; Lin, Xihong ; Shapiro, Geoffrey I. ; Jänne, Pasi A. ; Johnson, Bruce E. ; Meyerson, Matthew ; Kwiatkowski, David J. ; Castrillon, Diego H. ; Bardeesy, Nabeel ; Sharpless, Norman E. ; Wong, Kwok Kin. / LKB1 modulates lung cancer differentiation and metastasis. In: Nature. 2007 ; Vol. 448, No. 7155. pp. 807-810.
@article{1780f72bf95841eda553ae595b57e9c6,
title = "LKB1 modulates lung cancer differentiation and metastasis",
abstract = "Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34{\%} and 19{\%} of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.",
author = "Hongbin Ji and Ramsey, {Matthew R.} and Hayes, {D. Neil} and Cheng Fan and Kate McNamara and Piotr Kozlowski and Chad Torrice and Wu, {Michael C.} and Takeshi Shimamura and Perera, {Samanthi A.} and Liang, {Mei Chih} and Dongpo Cai and Naumov, {George N.} and Lei Bao and Contreras, {Cristina M.} and Danan Li and Liang Chen and Janakiraman Krishnamurthy and Jussi Koivunen and Chirieac, {Lucian R.} and Padera, {Robert F.} and Bronson, {Roderick T.} and Lindeman, {Neal I.} and Christiani, {David C.} and Xihong Lin and Shapiro, {Geoffrey I.} and J{\"a}nne, {Pasi A.} and Johnson, {Bruce E.} and Matthew Meyerson and Kwiatkowski, {David J.} and Castrillon, {Diego H.} and Nabeel Bardeesy and Sharpless, {Norman E.} and Wong, {Kwok Kin}",
year = "2007",
month = "8",
day = "16",
doi = "10.1038/nature06030",
language = "English (US)",
volume = "448",
pages = "807--810",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7155",

}

TY - JOUR

T1 - LKB1 modulates lung cancer differentiation and metastasis

AU - Ji, Hongbin

AU - Ramsey, Matthew R.

AU - Hayes, D. Neil

AU - Fan, Cheng

AU - McNamara, Kate

AU - Kozlowski, Piotr

AU - Torrice, Chad

AU - Wu, Michael C.

AU - Shimamura, Takeshi

AU - Perera, Samanthi A.

AU - Liang, Mei Chih

AU - Cai, Dongpo

AU - Naumov, George N.

AU - Bao, Lei

AU - Contreras, Cristina M.

AU - Li, Danan

AU - Chen, Liang

AU - Krishnamurthy, Janakiraman

AU - Koivunen, Jussi

AU - Chirieac, Lucian R.

AU - Padera, Robert F.

AU - Bronson, Roderick T.

AU - Lindeman, Neal I.

AU - Christiani, David C.

AU - Lin, Xihong

AU - Shapiro, Geoffrey I.

AU - Jänne, Pasi A.

AU - Johnson, Bruce E.

AU - Meyerson, Matthew

AU - Kwiatkowski, David J.

AU - Castrillon, Diego H.

AU - Bardeesy, Nabeel

AU - Sharpless, Norman E.

AU - Wong, Kwok Kin

PY - 2007/8/16

Y1 - 2007/8/16

N2 - Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.

AB - Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.

UR - http://www.scopus.com/inward/record.url?scp=34547926839&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547926839&partnerID=8YFLogxK

U2 - 10.1038/nature06030

DO - 10.1038/nature06030

M3 - Article

C2 - 17676035

AN - SCOPUS:34547926839

VL - 448

SP - 807

EP - 810

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7155

ER -