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Neuro Oncol. 2013 Oct;15(10):1317-29. doi: 10.1093/neuonc/not084. Epub 2013 Jun 27.

Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis.

Author information

1
Corresponding Author: C. Ryan Miller, MD, PhD, University of North Carolina School of Medicine, 6109B Neurosciences Research Building, Campus Box 7250, Chapel Hill, NC 27599-7250. rmiller@med.unc.edu.

Abstract

BACKGROUND:

Glioblastoma (GBM) genomes feature recurrent genetic alterations that dysregulate core intracellular signaling pathways, including the G1/S cell cycle checkpoint and the MAPK and PI3K effector arms of receptor tyrosine kinase (RTK) signaling. Elucidation of the phenotypic consequences of activated RTK effectors is required for the design of effective therapeutic and diagnostic strategies.

METHODS:

Genetically defined, G1/S checkpoint-defective cortical murine astrocytes with constitutively active Kras and/or Pten deletion mutations were used to systematically investigate the individual and combined roles of these 2 RTK signaling effectors in phenotypic hallmarks of glioblastoma pathogenesis, including growth, migration, and invasion in vitro. A novel syngeneic orthotopic allograft model system was used to examine in vivo tumorigenesis.

RESULTS:

Constitutively active Kras and/or Pten deletion mutations activated both MAPK and PI3K signaling. Their combination led to maximal growth, migration, and invasion of G1/S-defective astrocytes in vitro and produced progenitor-like transcriptomal profiles that mimic human proneural GBM. Activation of both RTK effector arms was required for in vivo tumorigenesis and produced highly invasive, proneural-like GBM.

CONCLUSIONS:

These results suggest that cortical astrocytes can be transformed into GBM and that combined dysregulation of MAPK and PI3K signaling revert G1/S-defective astrocytes to a primitive gene expression state. This genetically-defined, immunocompetent model of proneural GBM will be useful for preclinical development of MAPK/PI3K-targeted, subtype-specific therapies.

KEYWORDS:

Pten; astrocytes; genetically engineered mouse; glioblastoma; invasion

PMID:
23814263
PMCID:
PMC3779038
DOI:
10.1093/neuonc/not084
[Indexed for MEDLINE]
Free PMC Article
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