Journal ArticleDOI
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 Contreras,Danan Li,Liang Chen,Janakiraman Krishnamurthy,Jussi Koivunen,Lucian R. Chirieac,Robert 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 +33 more
TLDR
LKB1 is established as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis in lung cancer, and expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes as targets of LKB1 repression.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.read more
Citations
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Autophagy in the Pathogenesis of Disease
TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
Journal ArticleDOI
Regulation of cancer cell metabolism
TL;DR: Interest in the topic of tumour metabolism has waxed and waned over the past century, but it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
Journal ArticleDOI
AMPK phosphorylation of raptor mediates a metabolic checkpoint.
Dana M. Gwinn,David B. Shackelford,Daniel F. Egan,Maria M. Mihaylova,Annabelle Mery,Debbie S. Vasquez,Benjamin E. Turk,Reuben J. Shaw +7 more
TL;DR: AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor, uncovering a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.
Journal ArticleDOI
Molecular origins of cancer: Lung cancer
TL;DR: From the Departments of Thoracic/Head and Neck Medical Oncology and Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston.
Journal ArticleDOI
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression.
TL;DR: The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
References
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Rafael A. Irizarry,Bridget G. Hobbs,Francois Collin,Yasmin Beazer-Barclay,Kristen J. Antonellis,Uwe Scherf,Terence P. Speed +6 more
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