title: RHPN2 drives mesenchymal transformation in malignant glioma by triggering RhoA activation.
abstract: 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.
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Danussi
authors.forename: Uri David
authors.initials: UD
authors.lastname: Akavia
authors.forename: Francesco
authors.initials: F
authors.lastname: Niola
authors.forename: Andreja
authors.initials: A
authors.lastname: Jovic
authors.forename: Anna
authors.initials: A
authors.lastname: Lasorella
authors.forename: Dana
authors.initials: D
authors.lastname: Pe'er
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020742:rhoA GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C471419:RHPN2 protein, human; D020742:rhoA GTP-Binding Protein