PTEN dosage is essential for neurofibroma development and malignant transformation

Caroline Gregorian, Jonathan Nakashima, Sarah M. Dry, P. Leia Nghiemphu, Kate Barzan Smith, Yan Ao, Julie Dang, Gregory Lawson, Ingo K. Mellinghoff, Paul S. Mischel, Michael Phelps, Luis F. Parada, Xin Liu, Michael V. Sofroniew, Fritz C. Eilber, Hong Wu

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Patients with neurofibromatosis type 1 (NF1) carry approximately a 10% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST). Although the molecular mechanisms underlying NF1 to MPNST malignant transformation remain unclear, alterations of both the RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways have been implicated. In a series of genetically engineered murine models, we perturbed RAS/RAF/MAPK or/and PTEN/PI3K/AKT pathway, individually or simultaneously, via conditional activation of K-ras oncogene or deletion of Nf1 or Pten tumor suppressor genes. Only K-Ras activation in combination with a single Pten allele deletion led to 100% penetrable development of NF lesions and subsequent progression to MPNST. Importantly, loss or decrease in PTEN expression was found in all murine MPNSTs and a majority of human NF1-associated MPNST lesions, suggesting that PTEN dosage and its controlled signaling pathways are critical for transformation of NFs to MPNST. Using noninvasive in vivo PET-CT imaging, we demonstrated that FDG can be used to identify the malignant transformation in both murine and human MPNSTs. Our data suggest that combined inhibition of RAS/RAF/MAPK and PTEN/PI3K/AKT pathways may be beneficial for patients with MPNST.

Original languageEnglish (US)
Pages (from-to)19479-19484
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number46
DOIs
StatePublished - Nov 17 2009

Keywords

  • In vivo PET imaging
  • Peripheral nerve sheath tumor
  • Tumor suppressor

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'PTEN dosage is essential for neurofibroma development and malignant transformation'. Together they form a unique fingerprint.

Cite this