Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Miething, C; Scuoppo, C; Bosbach, B; Appelmann, I; Nakitandwe, J; Ma, J; Wu, G; Lintault, L; Auer, M; Premsrirut, PK; Teruya-Feldstein, J; Hicks, J; Benveniste, H; Speicher, MR; Downing, JR; Lowe, SW.
PTEN action in leukaemia dictated by the tissue microenvironment.
Nature. 2014; 510(7505):402-406
Doi: 10.1038/nature13239
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- Co-Autor*innen der Med Uni Graz
- Auer Martina
- Speicher Michael
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Chemokines - metabolism
- Gene Knockdown Techniques -
- Leukemia - enzymology Leukemia - genetics Leukemia - physiopathology
- Mice, Transgenic -
- PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism
- Phosphatidylinositol 3-Kinases - metabolism
- RNA Interference -
- Receptors, G-Protein-Coupled - metabolism
- Signal Transduction -
- Tumor Microenvironment - physiology