Miething, C., Scuoppo, C., Bosbach, B., Appelmann, I., Nakitandwe, J., Ma, J., Wu, G., Lintault, L., Auer, M., Premsrirut, P. K., Teruya-Feldstein, J., Hicks, J., Benveniste, H., Speicher, M. R., Downing, J. R., Lowe, S. W. (May 2014) PTEN action in leukaemia dictated by the tissue microenvironment. Nature, 510 (7505). p. 402. ISSN 0028-0836
Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN diseases & disorders > cancer > cancer types > leukemia |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics CSHL Cancer Center Shared Resources > Bioinformatics Service CSHL Cancer Center Shared Resources > Functional Genomics and Genetics Service CSHL Cancer Center Shared Resources > Instrumentation Service CSHL Cancer Center Shared Resources > Next Generation Sequencing Service CSHL labs > Hicks lab CSHL labs > Lowe lab School of Biological Sciences > Publications |
| Depositing User: | Matt Covey |
| Date: | 4 May 2014 |
| Date Deposited: | 15 May 2014 18:46 |
| Last Modified: | 16 Jul 2021 19:59 |
| PMCID: | PMC4165899 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/30141 |
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