Conditional astroglial Rictor overexpression induces malignant glioma in mice.
BACKGROUND
Hyperactivation of the mTORC2 signaling pathway has been shown to contribute to the oncogenic properties of gliomas. Moreover, overexpression of the mTORC2 regulatory subunit Rictor has been associated with increased proliferation and invasive character of these tumor cells.


RESULTS
To determine whether Rictor overexpression was sufficient to induce glioma formation in mice, we inserted a Cre-lox-regulated human Rictor transgene into the murine ROSA26 locus. This floxed Rictor strain was crossed with mice expressing the Cre recombinase driven from the glial fibrillary acidic protein (GFAP) promoter whose expression is limited to the glial cell compartment. Double transgenic GFAP-Cre/Rictor(loxP/loxP) mice developed multifocal infiltrating glioma containing elevated mTORC2 activity and typically involved the subventricular zone (SVZ) and lateral ventricle. Analysis of Rictor-dependent signaling in these tumors demonstrated that in addition to elevated mTORC2 activity, an mTORC2-independent marker of cortical actin network function, was also elevated. Upon histological examination of the neoplasms, many displayed oligodendroglioma-like phenotypes and expressed markers associated with oligodendroglial lineage tumors. To determine whether upstream oncogenic EGFRvIII signaling would alter tumor phenotypes observed in the GFAP-Cre/Rictor(loxP/loxP) mice, transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor(loxP/loxP) mice were generated. These mice developed mixed astrocytic-oligodendroglial tumors, however glioma formation was accelerated and correlated with increased mTORC2 activity. Additionally, the subventricular zone within the GFAP-Cre/Rictor(loxP/loxP) mouse brain was markedly expanded, and a further proliferation within this compartment of the brain was observed in transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor(loxP/loxP) mice.


CONCLUSIONS
These data collectively establish Rictor as a novel oncoprotein and support the role of dysregulated Rictor expression in gliomagenesis via mTOR-dependent and mTOR-independent mechanisms. Furthermore, oncogenic EGFRvIII signaling appears to potentiate the in vivo proliferative capacity of GFAP-Cre/Rictor(loxP/loxP) gliomas.
Department of Research and Development, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California, United States of America.
Tariq
T
Bashir
Cheri
C
Cloninger
Nicholas
N
Artinian
Lauren
L
Anderson
Andrew
A
Bernath
Brent
B
Holmes
Angelica
A
Benavides-Serrato
Nesrin
N
Sabha
Robert N
RN
Nishimura
Abhijit
A
Guha
Joseph
J
Gera
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D022661:RNA, Untranslated; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C410723:epidermal growth factor receptor VIII; C525637:rictor protein, mouse; D066246:ErbB Receptors; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases