PTEN action in leukaemia dictated by the tissue microenvironment
| Autor: | Benedikt Bosbach, Michael R. Speicher, Helene Benveniste, Joy Nakitandwe, Jing Ma, James R. Downing, Martina Auer, Claudio Scuoppo, Iris Appelmann, Gang Wu, Scott W. Lowe, Cornelius Miething, James W. Hicks, Prem K. Premsrirut, Laura Lintault, Julie Teruya-Feldstein |
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| Rok vydání: | 2014 |
| Předmět: |
Mice
Transgenic Biology Phosphatidylinositol 3-Kinases Article Receptors G-Protein-Coupled chemistry.chemical_compound Tumor Microenvironment Animals Gene silencing PTEN Phosphatidylinositol Protein kinase B PI3K/AKT/mTOR pathway Tumor microenvironment Leukemia Multidisciplinary PTEN Phosphohydrolase Haematopoiesis chemistry Gene Knockdown Techniques Cancer research biology.protein RNA Interference Chemokines Signal Transduction |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature13239 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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