Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma
Seçkin Akgül,
Yinghua Li,
Siyuan Zheng,
Marcel Kool,
Daniel M. Treisman,
Chaoyang Li,
Yuan Wang,
Susanne Gröbner,
Tsuneo Ikenoue,
Yiping Shen,
Sandra Camelo-Piragua,
Gerald Tomasek,
Sebastian Stark,
Vinay Guduguntla,
James F. Gusella,
Kun-Liang Guan,
Stefan M. Pfister,
Roel G.W. Verhaak,
Yuan Zhu
Affiliations
Seçkin Akgül
Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children’s National Medical Center, Washington, DC 20010, USA; Sid Faithfull Brain Cancer Research Laboratory, Cell & Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
Yinghua Li
Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children’s National Medical Center, Washington, DC 20010, USA
Siyuan Zheng
Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Marcel Kool
Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
Daniel M. Treisman
Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children’s National Medical Center, Washington, DC 20010, USA
Chaoyang Li
Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children’s National Medical Center, Washington, DC 20010, USA
Yuan Wang
Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children’s National Medical Center, Washington, DC 20010, USA
Susanne Gröbner
Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
Tsuneo Ikenoue
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
Yiping Shen
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Sandra Camelo-Piragua
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Gerald Tomasek
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Sebastian Stark
Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
Vinay Guduguntla
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
James F. Gusella
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Kun-Liang Guan
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA
Stefan M. Pfister
Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Department of Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany
Roel G.W. Verhaak
Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA
Yuan Zhu
Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gilbert Family Neurofibromatosis Institute, Children’s National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children’s National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children’s National Medical Center, Washington, DC 20010, USA; Corresponding author
Summary: Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively. : Hyperactivation of PI3K/AKT signaling is frequently observed in adult glioblastomas (GBMs), whereas sonic hedgehog-subgroup medulloblastomas (SHH-MBs) in children rarely exhibit AKT activation. Using a genetically engineered mouse model of malignant brain tumor, Akgül et al. show that Rictor/mTORC2 loss inhibits Akt signaling, which delays p53-mutant-driven malignant gliomas, while promoting SHH-MBs. Keywords: glioblastoma, medulloblastoma, Rictor, mammalian target of rapamycin complex 2, mTORC2, Pten, p53, phosphatidylinositol 3-kinase pathway, PI3K, Akt
