Publications by authors named "Kosuke Funato"

10 Publications

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Dissecting the impact of regional identity and the oncogenic role of human-specific NOTCH2NL in an hESC model of H3.3G34R-mutant glioma.

Cell Stem Cell 2021 Feb 17. Epub 2021 Feb 17.

Department of Neurosurgery, Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cancer Biology and Genetics, Sloan Kettering Institute, New York, NY 10065, USA. Electronic address:

H3.3G34R-mutant gliomas are lethal tumors of the cerebral hemispheres with unknown mechanisms of regional specificity and tumorigenicity. We developed a human embryonic stem cell (hESC)-based model of H3.3G34R-mutant glioma that recapitulates the key features of the tumors with cell-type specificity to forebrain interneuronal progenitors but not hindbrain precursors. We show that H3.3G34R, ATRX, and TP53 mutations cooperatively impact alternative RNA splicing events, particularly suppression of intron retention. This leads to increased expression of components of the Notch pathway, notably NOTCH2NL, a human-specific gene family. We also uncover a parallel mechanism of enhanced NOTCH2NL expression via genomic amplification of its locus in some H3.3G34R-mutant tumors. These findings demonstrate a novel mechanism whereby evolutionary pathways that lead to larger brain size in humans are co-opted to drive tumor growth.
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http://dx.doi.org/10.1016/j.stem.2021.02.003DOI Listing
February 2021

Adult Human Glioblastomas Harbor Radial Glia-like Cells.

Stem Cell Reports 2020 02 30;14(2):338-350. Epub 2020 Jan 30.

Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Radial glia (RG) cells are the first neural stem cells to appear during embryonic development. Adult human glioblastomas harbor a subpopulation of RG-like cells with typical RG morphology and markers. The cells exhibit the classic and unique mitotic behavior of normal RG in a cell-autonomous manner. Single-cell RNA sequencing analyses of glioblastoma cells reveal transcriptionally dynamic clusters of RG-like cells that share the profiles of normal human fetal radial glia and that reside in quiescent and cycling states. Functional assays show a role for interleukin in triggering exit from dormancy into active cycling, suggesting a role for inflammation in tumor progression. These data are consistent with the possibility of persistence of RG into adulthood and their involvement in tumor initiation or maintenance. They also provide a putative cellular basis for the persistence of normal developmental programs in adult tumors.
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http://dx.doi.org/10.1016/j.stemcr.2020.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014025PMC
February 2020

Target identification reveals lanosterol synthase as a vulnerability in glioma.

Proc Natl Acad Sci U S A 2019 04 28;116(16):7957-7962. Epub 2019 Mar 28.

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065;

Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain tumor for which novel therapeutic approaches are desperately needed. Previous studies have shown that the menin inhibitor MI-2 exhibits promising activity in preclinical DIPG and adult glioma models, although the mechanism underlying this activity is unknown. Here, using an integrated approach, we show that MI-2 exerts its antitumor activity in glioma largely independent of its ability to target menin. Instead, we demonstrate that MI-2 activity in glioma is mediated by disruption of cholesterol homeostasis, with suppression of cholesterol synthesis and generation of the endogenous liver X receptor ligand, 24,25-epoxycholesterol, resulting in cholesterol depletion and cell death. Notably, this mechanism is responsible for MI-2 activity in both DIPG and adult glioma cells. Metabolomic and biochemical analyses identify lanosterol synthase as the direct molecular target of MI-2, revealing this metabolic enzyme as a vulnerability in glioma and further implicating cholesterol homeostasis as an attractive pathway to target in this malignancy.
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http://dx.doi.org/10.1073/pnas.1820989116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475387PMC
April 2019

SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity.

EMBO Rep 2018 11 13;19(11). Epub 2018 Sep 13.

Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells, including glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C-terminal lysine residues. Our results suggest that SIRT2-mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of glioblastoma.
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http://dx.doi.org/10.15252/embr.201745587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6216266PMC
November 2018

Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma.

PLoS One 2016 6;11(10):e0162978. Epub 2016 Oct 6.

Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.

Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh.10 gene transfer vector. The data demonstrates that single, local delivery of an anti-EGFR antibody by an AAVrh.10 vector coding for cetuximab (AAVrh.10Cetmab) reduces GBM tumor growth and increases survival in xenograft mouse models of a human GBM EGFR-expressing cell line and patient-derived GBM. AAVrh10.CetMab-treated mice displayed a reduction in cachexia, a significant decrease in tumor volume and a prolonged survival following therapy. Adeno-associated-directed delivery of a gene encoding a therapeutic anti-EGFR monoclonal antibody may be an effective strategy to treat GBM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053413PMC
June 2017

The RNA Binding Protein Mex-3B Is Required for IL-33 Induction in the Development of Allergic Airway Inflammation.

Cell Rep 2016 08 18;16(9):2456-71. Epub 2016 Aug 18.

Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address:

Allergic airway inflammation is one of the primary features of allergic asthma. Interleukin-33 (IL-33) is recognized as a key pro-inflammatory cytokine that mediates allergic airway inflammation, and its expression is elevated in this condition, but little is known about the regulatory mechanisms underlying IL-33 induction. Here, we show that the RNA binding protein Mex-3B plays a critical role in the induction of IL-33 in the development of allergic airway inflammation. We generated Mex3b(-/-) mice and found that they develop significantly less airway inflammation than wild-type mice due to reduced induction of IL-33. Furthermore, we show that Mex-3B directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33. Moreover, we show that inhalation of an antisense oligonucleotide targeting Mex-3B suppresses allergic airway inflammation. Our data identify a signaling pathway that post-transcriptionally regulates IL-33 expression and suggest that Mex-3B could be a promising molecular target for the treatment of allergic asthma.
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http://dx.doi.org/10.1016/j.celrep.2016.07.062DOI Listing
August 2016

Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation.

Science 2014 Dec 20;346(6216):1529-33. Epub 2014 Nov 20.

Department of Neurosurgery, Center for Stem Cell Biology and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice.
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http://dx.doi.org/10.1126/science.1253799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995593PMC
December 2014

Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma.

Cancer Gene Ther 2015 Jan 12;22(1):1-8. Epub 2014 Dec 12.

Department of Genetic Medicine Weill Cornell Medical College, New York, New York.

The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti-angiogenesis monoclonal antibody.
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http://dx.doi.org/10.1038/cgt.2014.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293257PMC
January 2015

Tyrosine phosphatase PTPRD suppresses colon cancer cell migration in coordination with CD44.

Exp Ther Med 2011 May 21;2(3):457-463. Epub 2011 Mar 21.

Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.

PTPRD is a receptor-type tyrosine-protein phosphatase. Recent analyses of comprehensive mutations and copy numbers have revealed that PTPRD is frequently mutated and homozygously deleted in various types of cancer, including glioblastoma, melanoma, breast and colon cancer. However, the molecular functions of PTPRD in cancer progression have yet to be elucidated. Herein, PTPRD suppressed colon cancer cell migration and was required for appropriate cell-cell adhesion. In addition, PTPRD regulated cell migration in cooperation with β-catenin/TCF signaling and its target CD44. Furthermore, expression levels of PTPRD were down-regulated in highly invasive cancers and were significantly correlated with patient survival. Our findings suggest that PTPRD is required for colon cancer invasion and progression.
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http://dx.doi.org/10.3892/etm.2011.231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440690PMC
May 2011