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

Kun-Wei Liu1, Haizhong Feng, Robert Bachoo

  • 1University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.

The Journal of Clinical Investigation
|March 12, 2011
PubMed

Insights

Platelet-derived growth factor receptor α (PDGFRA) activation drives glioblastoma in cells lacking p16INK4a/p14ARF. SHP-2 regulates this process via PI3K/AKT/mTOR signaling, identifying SHP-2 as a potential glioblastoma therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Malignant glioblastomas are subclassified into 4 subtypes based on genetic lesions.
  • One subtype shows Platelet-Derived Growth Factor Receptor α (PDGFRA) overexpression and Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) locus loss.
  • The CDKN2A locus encodes P16INK4a and P14ARF tumor suppressors.

Purpose of the Study:

  • To investigate the role of PDGFRα activation in glioblastoma development.
  • To elucidate the molecular mechanisms underlying PDGFRα-driven tumorigenesis in the context of Ink4a/Arf deficiency.
  • To identify potential therapeutic targets for glioblastoma treatment.

Main Methods:

  • Activation of PDGFRα in Ink4a/Arf-deficient mouse astrocytes and human glioma cells.
  • Assessing the impact of p16INK4a or p19ARF restoration on PDGFRα-promoted glioma formation.
  • Investigating the role of SHP-2 and PI3K binding to PDGFRα in tumorigenesis.
  • Utilizing shRNAs and pharmacological inhibitors to target SHP-2.
  • Examining downstream AKT/mTOR activation.
  • Analyzing co-expression of PDGFRα and PDGF-A in clinical glioblastoma specimens.

Main Results:

  • PDGFRα activation conferred tumorigenicity to Ink4a/Arf-deficient cells.
  • Restoration of p16INK4a, but not p19ARF, suppressed PDGFRα-promoted glioma formation.
  • Disruption of PDGFRα binding to SHP-2 or PI3K diminished tumorigenesis.
  • SHP-2 inhibition impaired tumorigenesis by disrupting PI3K interaction and suppressing AKT/mTOR activation.
  • Activated PI3K expression rescued the effect of SHP-2 inhibition.
  • PDGFRα and PDGF-A co-expression in glioblastomas correlated with SHP-2/AKT/mTOR signaling activation.

Conclusions:

  • In Ink4a/Arf-deficient glioblastomas, overexpressed PDGFRα promotes tumorigenesis via the SHP-2-regulated PI3K/AKT/mTOR pathway.
  • These findings validate genomic subclassification of glioblastomas.
  • SHP-2 is identified as a potential therapeutic target for glioblastoma treatment.

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