SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans

University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 02/2011; 121(3):905-17. DOI: 10.1172/JCI43690
Source: PubMed


Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor α (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFRα conferred tumorigenicity to Ink4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFRα-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFRα, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFRα and PDGF-A are coexpressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas.

Download full-text


Available from: Andrius Kazlauskas
  • Source
    • "miRNA326 0.0002 1.58 times Maintenance and survival of striatal precursor pool TGM7 [16] [17] miRNA181c 0.0029 1.50 times Switch for lineage-to-self-renewal and telomerase expression PTPN11, PTPN22, DUSP6, PBX3, IRF8, and ZEB2 [18] [19] [20] [21] "
    [Show abstract] [Hide abstract]
    ABSTRACT: The striatum is considered to be the central processing unit of the basal ganglia in locomotor activity and cognitive function of the brain. IGF-1 could act as a control switch for the long-term proliferation and survival of EGF + bFGF-responsive cultured embryonic striatal stem cell (ESSC), while LIF imposes a negative impact on cell proliferation. The IGF-1-treated ESSCs also showed elevated hTERT expression with demonstration of self-renewal and trilineage commitment (astrocytes, oligodendrocytes, and neurons). In order to decipher the underlying regulatory microRNA (miRNA)s in IGF-1/LIF-treated ESSC-derived neurogenesis, we performed in-depth miRNA profiling at 12 days in vitro and analyzed the candidates using the Partek Genome Suite software. The annotated miRNA fingerprints delineated the differential expressions of miR-143, miR-433, and miR-503 specific to IGF-1 treatment. Similarly, the LIF-treated ESSCs demonstrated specific expression of miR-326, miR-181, and miR-22, as they were nonsignificant in IGF-treated ESSCs. To elucidate the possible downstream pathways, we performed in silico mapping of the said miRNAs into ingenuity pathway analysis. Our findings revealed the important mRNA targets of the miRNAs and suggested specific interactomes. The above studies introduced a new genre of miRNAs for ESSC-based neuroregenerative therapeutic applications.
    Full-text · Article · Sep 2014 · BioMed Research International
  • Source
    • "Indeed the most common alterations in GBM include amplification of RTK receptors, such as EGFR and PDGFRA, and increased expression of ligands, such as PDGFB [5, 10-12]. Furthermore, overexpression of ligands such as PDGFB can drive tumorigenesis in murine brain tumor models [13-15]. Despite the role of RTKs in driving oncogenesis, small molecule inhibitors targeting single RTK pathways have been largely unsuccessful in improving overall survival [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma (GBM), a highly malignant brain tumor of adults and children, diffusely invades within the non-neoplastic brain. Despite aggressive current therapeutic interventions, improved therapeutic strategies are greatly needed. Interactions between the tumor and constituents of its microenvironment are known to regulate malignancy, and heparan sulfate proteoglycans (HSPGs) are important as they bind diverse extracellular proteins, including growth factors and cell adhesion molecules, regulating the activity of several ligand-mediated signaling pathways. Recent work from our group described a mechanism by which GBM regulates PDGFR-alpha signaling via enzymatic alteration of heparan sulfate proteoglycans (HSPGs) in the extracellular microenvironment. Blocking tumor-induced alterations of HSPGs, which can be achieved by pharmacological strategies, would potentially inhibit multiple oncogenic signaling pathways in tumor cells and disrupt critical tumormicroenvironment interactions. Here we examine HSPGs and the enzymes that modify them in GBM. We compare their expression across tumor subtypes, their potential roles in oncogenesis, and their potential as novel therapeutic targets in GBM.
    Full-text · Article · May 2012 · Oncotarget
  • Source
    • "EGFR amplification/ overexpression and constitutively active mutation are common genetic lesions in human glioblastoma, and are frequently accompanied by Ink4a/Arf deletion which impairs both the p53 and Rb signaling pathways. Constitutively active EGFR and PDGFRα overexpression are individually insufficient for tumorigenesis, but each can cooperate with Ink4a/Arf deletion to induce formation of glioma-like lesions (Holland et al., 1998; Liu et al., 2011b; Zhu et al., 2009). These models provide experimental evidence of the strong selective advantage imparted by disrupting PI3K, Rb and p53 signaling pathways, consistent with the mutation analysis of human tumors shown later (Parsons et al., 2008; TCGA, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: S. L. Rankin, G. Zhu and S. J. Baker (2012) Neuropathology and Applied Neurobiology38, 254–270 Insights gained from modelling high-grade glioma in the mouse High-grade gliomas (HGGs) are devastating primary brain tumours with poor outcomes. Advances towards effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumour initiation, progression and phenotype, the influence of tumour micro-environment, and the analysis of cell types that can give rise to glioma. HGGs are a heterogeneous group of tumours, and the complexity of diverse mutations within common signalling pathways as well as the developmental and cell-type context of transformation contributes to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely simulate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing.
    Preview · Article · Oct 2011 · Neuropathology and Applied Neurobiology
Show more