Publication Date:
2014-05-09
Description:
PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165899/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165899/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miething, Cornelius -- Scuoppo, Claudio -- Bosbach, Benedikt -- Appelmann, Iris -- Nakitandwe, Joy -- Ma, Jing -- Wu, Gang -- Lintault, Laura -- Auer, Martina -- Premsrirut, Prem K -- Teruya-Feldstein, Julie -- Hicks, James -- Benveniste, Helene -- Speicher, Michael R -- Downing, James R -- Lowe, Scott W -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA087497/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- S10 OD016282/OD/NIH HHS/ -- U01 CA105388/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 19;510(7505):402-6. doi: 10.1038/nature13239. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Department of Medicine I, Medical Center - University of Freiburg, 79106 Freiburg, Germany. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Howard Hughes Medical Institute, New York, New York 10065, USA. ; Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria. ; Departments of Anesthesiology and Radiology, Stony Brook University, Stony Brook, New York 11794, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805236" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Chemokines/metabolism
;
Gene Knockdown Techniques
;
Leukemia/*enzymology/genetics/*physiopathology
;
Mice, Transgenic
;
PTEN Phosphohydrolase/*genetics/*metabolism
;
Phosphatidylinositol 3-Kinases/metabolism
;
RNA Interference
;
Receptors, G-Protein-Coupled/metabolism
;
Signal Transduction
;
Tumor Microenvironment/*physiology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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