Background. Human gliomas account for the most common and malignant tumors in the central nervous system (CNS). Despite optimal treatments, survival of patients with high-grade glioblastoma multiforme (GBM) remains poor. Recent coordinated genomic analyses of a large cohort of clinical GBM specimens identified frequent co-alterations of genes in three core pathways—the P53, retinoblastoma (RB), and receptor tyrosine kinase (RTK) pathways that are crucial in gliomagenesis. Further multi-institutional efforts have sub-classified GBMs into four clinical relevant subtypes based on their signature genetic lesions. Among them, PDGFRA overexpression is concomitant with a loss of CDKN2A locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of GBMs. To better understand and design therapeutic strategies against gliomas driven by abnormal platelet-derived growth factor (PDGF) signaling, functional studies using human or mouse models are needed.

Major findings. In order to establish a model that allows us to assess contributions of different signaling pathways to PDGFRα-induced glioma formation, we generated Ink4a/Arf-deficient primary mouse astrocytes (referred to as mAst hereafter) and human glioma cells that overexpress PDGFRα and/or PDGF-A. We found that activation of PDGFRα confers tumorigenicity to Ink4a/Arf-deficient mAst and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF by retroviral transduction suppresses PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SH-2-containing phosphotyrosine phosphatase SHP-2 or Phosphoinositol 3'-Kinase (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. In clinical glioblastoma specimens, PDGFRα and PDGF-A are co-expressed and such co-expression is linked with activation of SHP-2/AKT/mTOR-signaling. Our data thus suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity.

Significance. We expect these findings will improve our understanding of the formation of the gliomas with PDGFRA and INK4A/ARF aberrations. There were studies that predicted SHP-2/PTPN11 as one of the linker genes in clinical GBMs that interact with multiple commonly altered genes. Our results functionally validate this hypothesis and identify SHP-2 as a converge point of several signaling pathways such as PDGFR, EGFR, PI3K, and mTOR that are frequently deregulated in GBMs. It thus represents a promising target for treatments against this fatal disease.