RHPN2 Drives Mesenchymal Transformation in Malignant Glioma by Triggering RhoA Activation

Details

• Alternative Title:
  Cancer Res
• Personal Author:
  Danussi, Carla ; Akavia, Uri David ; Niola, Francesco ; Jovic, Andreja ; Lasorella, Anna ; Pe’er, Dana ; Iavarone, Antonio
• Description:
  Mesenchymal transformation is a hallmark of aggressive glioblastoma (GBM). Here, we report the development of an unbiased method for computational integration of copy number variation, expression, and mutation data from large datasets. Using this method, we identified rhophilin 2 (RHPN2) as a central genetic determinant of the mesenchymal phenotype of human GBM. Notably, amplification of the human RHPN2 gene on chromosome 19 correlates with a dramatic decrease in the survival of patients with glioma. Ectopic expression of RHPN2 in neural stem cells and astrocytes triggered the expression of mesenchymal genes and promoted an invasive phenotype without impacting cell proliferation. Mechanistically, these effects were implemented through RHPN2-mediated activation of RhoA, a master regulator of cell migration and invasion. Our results define RHPN2 amplification as a central genetic determinant of a highly aggressive phenotype that directs the worst clinical outcomes in patients with GBM.
• Subjects:
  Adaptor Proteins, Signal Transducing Animals Article Astrocytes Cell Growth Processes Cell Line, Tumor Cell Movement Cell Transformation, Neoplastic Chromosomes, Human, Pair 19 DNA Copy Number Variations Gene Expression Regulation, Neoplastic Glioblastoma HEK293 Cells Humans Mesenchymal Stromal Cells Mice Mutation Neoplasm Invasiveness Neural Stem Cells Phenotype RhoA GTP-Binding Protein

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• Source:
  Cancer Res. 73(16):5140-5150.
• Pubmed ID:
  23774217
• Pubmed Central ID:
  PMC3805507
• Document Type:
  Journal Article
• Funding:
  5U54CA121852-08/CA/NCI NIH HHS/United States ; CA164729-01/CA/NCI NIH HHS/United States ; DP20D2414-1/DP/NCCDPHP CDC HHS/United States ; R01 CA085628/CA/NCI NIH HHS/United States ; R01 CA127643/CA/NCI NIH HHS/United States ; R01 CA164729/CA/NCI NIH HHS/United States ; R01 NS061776/NS/NINDS NIH HHS/United States ; R01CA085628/CA/NCI NIH HHS/United States ; R01CA101644/CA/NCI NIH HHS/United States ; R01CA127643/CA/NCI NIH HHS/United States ; R01CA131126/CA/NCI NIH HHS/United States ; R01NS061776/NS/NINDS NIH HHS/United States
• Volume:
  73
• Issue:
  16
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:d68031b21a08c786cea5d006da8458e1af1ac7fbad7a04346d1f2f4db1fb5539
• Download URL:
  https://stacks.cdc.gov/view/cdc/29761/cdc_29761_DS1.pdf
• File Type:
  [PDF - 2.51 MB ]