PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing1,2,3. 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 mTOR2. 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.
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European Nucleotide Archive
Data sets from RNA-seq analysis were deposited at the Sequence Read Archive (SRA) at the European Nucleotide Archive under the accession number PRJEB5498.
We are grateful to J. Cappellani, D. Grace, J. Simon and M. Taylor for technical assistance, S.-Y. Kim for performing tetraploid embryo complementation, J. Cheng for RNA-seq analysis, M. Riggs for CGH array analysis, M. Lupu and C. Le for MRI imaging, V. Longo and P. Zanzonico for PET analysis, J. Pichardo for data management, L. Lopez and A. Giri for tissue microarray construction, M. Saborowski for help with IHC staining, A. Roselló-Díez and M. Asher for expertise in antibody staining characterization and C. Sherr for constructive comments and editorial advice. We thank J. Jaen, M. Penfold and M. Walters from ChemoCentryx for providing the CCR9 small molecule inhibitor. C.M. was supported by a fellowship from the DFG (Mi1210/1-1). I.A. received support by a fellowship from the Deutsche Krebshilfe (DKH no. 109902). C.S. was supported by the Angel Foundation with a Curt Engelhorn fellowship. This work was also supported by a program project grant from the National Cancer Institute, a Leukemia and Lymphoma Society Specialized Center of Research, and philanthropic funds from the Don Monti Foundation. S.W.L. is supported by the Geoffrey Beene Foundation and is an investigator at the Howard Hughes Medical Institute.
Extended data figures
3D reconstruction of 18F-FDG PET/CT imaging of a mouse with PTEN-inactivated shPten T-ALL (without Dox treatment)
18F-FDG uptake at 12 days after transplantation with 1x105 shPten T-ALL cells without Dox treatment (PTEN knocked down) was measured by combined PET/CT imaging on a Inveon MicroPET/CT system (Siemens, NY, USA). 3D reconstruction was performed using the Inveon Workplace software package (Siemens Medical Solutions USA, PA, USA). Significant uptake was observed in the intestine, liver and spleen. Additionally, there is physiologic tracer enrichment in the heart and bladder.
3D reconstruction of 18F-FDG PET/CT imaging of a mouse with PTEN-reactivated shPten T-ALL (with Dox treatment)
18F-FDG uptake at 12 days after transplantation with 1x105 shPten T-ALL cells (4 days after begin of Dox treatment to reexpress PTEN) was measured by combined PET/CT imaging on a Inveon MicroPET/CT system (Siemens, NY, USA). 3D reconstruction was performed using the Inveon Workplace software package (Siemens Medical Solutions USA, PA, USA). Significant uptake was observed in the spleen, whereas liver and intestine show only a weak signal. Also in the Dox treated mice, there is physiologic tracer enrichment in the heart and bladder.
About this article
Frontiers in Immunology (2018)