epigenetic drug development based on hierarchy and plasticity of malignant brain tumors

• Project/Area Number: 24390341
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Nagoya University
• Principal Investigator: NATSUME Atsushi 名古屋大学, 医学(系)研究科(研究院), 准教授 (30362255)
• Co-Investigator(Kenkyū-buntansha): WAKABAYASHI Toshihiko 名古屋大学, 医学系研究科, 教授 (50220835)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2014: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2012: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
• Keywords: 脳腫瘍 / 悪性脳腫瘍 / ゲノム / エピジェネティクス / マウス / ポリコーム / 次世代シークエンス

Outline of Final Research Achievements

Here, combining high-throughput sequencing data of 757 cases from two large cohorts of grade-II/III gliomas, we delineated the entire picture of genetic alterations and affected pathways in grade-II/III gliomas with sensitive detection of driver genes. Grade-II/III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive/negative correlations and chronological hierarchy as inferred from different allelic burdens among coexisting mutations, suggesting functional interplays between mutations that drive clonal selection. Extensive serial/multi-regional sampling analyses further supported this and also revealed high degrees of temporal/spatial heterogeneity generated during tumor expansion and relapse, which should be shaped by complex, but ordered processes of multiple clonal selections/evolutions.

Research Products

• [Journal Article] Mutational landscape and clonal architecture in grade II and III gliomas (2015)
  • Author(s): Suzuki H, Aoki K, Natsume A, Ogawa S. et al.
  • Journal Title: Nat Genet. Volume: 47 Issue: 5 Pages: 458-468
  • DOI: 10.1038/ng.3273
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Paired related homeobox 1 is associated with the invasive properties of glioblastoma cells. (2015)
  • Author(s): Sugiyama M, Hasegawa H, Ito S, Sugiyama K, Maeda M, Aoki K, Wakabayashi T, Hamaguchi M, Natsume A, Senga T.
  • Journal Title: Oncol Rep. Volume: 33 Issue: 3 Pages: 1123-30
  • DOI: 10.3892/or.2014.3681
  • Peer Reviewed
• [Journal Article] Effectiveness of plasma treatment on gastric cancer cells. (2015)
  • Author(s): Torii K, Yamada S, Nakamura K, Tanaka H, Kajiyama H, Tanahashi K, Iwata N, Kanda M, Kobayashi D, Tanaka C, Fujii T, Nakayama G, Koike M, Sugimoto H, Nomoto S, Natsume A, Fujiwara M, Mizuno M, Hori M, Saya H, Kodera Y
  • Journal Title: Gastric Cancer Volume: 20 Pages: 100-100
  • Peer Reviewed
• [Journal Article] Assessment of tumor cells in a mouse model of diffuse infiltrative glioma by Raman spectroscopy. (2014)
  • Author(s): Tanahashi K, Natsume A, Ohka F, Momota H, Kato A, Motomura K, Watabe N, Muraishi S, Nakahara H, Saito Y, Takeuchi I, Wakabayashi T
  • Journal Title: Biomed Res Int Volume: 20 Pages: 860241-860241
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Olig2 labeling index is correlated with histological and molecular classifications in low-grade diffuse gliomas. (2014)
  • Author(s): Suzuki A, Nobusawa S, Natsume A, Suzuki H, Kim YH, Yokoo H, Nagaishi M, Ikota H, Nakazawa T, Wakabayashi T, Ohgaki H, Nakazato Y.
  • Journal Title: J Neurooncol. Volume: 120 Issue: 2 Pages: 283-91
  • DOI: 10.1007/s11060-014-1568-1
  • Peer Reviewed
• [Journal Article] Novel somatic and germline mutations in intracranial germ cell tumours. (2014)
  • Author(s): Wang L, Yamaguchi S, Burstein MD, Terashima K, Chang K, Ng HK, Nakamura H, He Z, Doddapaneni H, Lewis L, Wang M, Suzuki T, Nishikawa R, Natsume A, Terasaka S, Dauser R, Whitehead W, Adekunle A, Sun J, Qiao Y, Marth G, Muzny DM, Gibbs RA, Leal SM, Wheeler DA, Lau CC.
  • Journal Title: Nature Volume: 511 Issue: 7508 Pages: 241-245
  • DOI: 10.1038/nature13296
  • Peer Reviewed
• [Journal Article] Association of dorsal inferior frontooccipital fasciculus fibers in the deep parietal lobe with both reading and writing processes: a brain mapping study. (2014)
  • Author(s): Motomura K, Fujii M, Maesawa S, Kuramitsu S, Natsume A, Wakabayashi T.
  • Journal Title: J Neurosurg. Volume: 1 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. (2014)
  • Author(s): Ohka F, Ito M, Ranjit M, Senga T, Motomura A, Motomura K, Saito K, Kato K, Kato Y, Wakabayashi T, Soga T, Natsume A.
  • Journal Title: Tumour Biol. Volume: 1 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Blockade of gap junction hemichannel protects secondary spinal cord injury from activated microglia-mediated glutamate exito-neurotoxicity. (2014)
  • Author(s): Umebayashi D, Natsume A, Takeuchi H, Hara M, Nishimura Y, Fukuyama R, Sumiyoshi N, Wakabayashi T.
  • Journal Title: J Neurotrauma. Volume: 1 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase-siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. (2014)
  • Author(s): Tsujiuchi T, Natsume A, Motomura K, Kondo G, Ranjit M, Hachisu R, Sugimura I, Tomita S, Takehara I, Woolley M, Barua NU, Gill SS, Bienemann AS, Yamashita Y, Toyokuni S, Wakabayashi T.
  • Journal Title: Am J Transl Res. Volume: 15 Pages: 169-178
  • Peer Reviewed
• [Journal Article] Lack of presence of the human cytomegalovirus in human glioblastoma. (2013)
  • Author(s): Yamashita Y, Ito Y, Isomura H, Takemura N, Okamoto A, Motomura K, Tsujiuchi T, Natsume A, Wakabayashi T, Toyokuni S, Tsurumi T
  • Journal Title: Mod Pathol Volume: Dec 13 Issue: 7 Pages: 922-9
  • DOI: 10.1038/modpathol.2013.219
  • Peer Reviewed
• [Journal Article] Immunohistochemical analysis-based proteomic subclassification of newly diagnosed glioblastomas. (2012)
  • Author(s): Motomura K, Natsume A, Watanabe R, Ito l, Kato Y, Momota H, Nishikawa R, Mishima K, Nakasu Y; Abe I, Namba H, Nakazato Y, Tashiro H, Takeuchi I, Mori T, Wakabayashi T.
  • Journal Title: Cancer Sci. Volume: 103 Pages: 1871-9
  • Peer Reviewed
• [Journal Article] Contribution of microRNA-1275 to Claudinll protein suppression via apolycomb-mediated silencing mechanism in human glioma stem-like cellS. (2012)
  • Author(s): Katsushima K, Shinjo K, Natsume A, Ohka F, Fujii M, Osada H, Sekido y Kondo Y.
  • Journal Title: J Biol Chem. Volume: 287 Pages: 27396-406
  • Peer Reviewed
• [Journal Article] Girdin maintains the sternness of glioblastoma stem cells. (2012)
  • Author(s): Natsume A, Kato T, Kinjo S, Enomoto A, Toda H, Shimato S, Ohka F, Motomura K, Kondo Y, Miyata T, Takahashi M, Wakabayashi T.
  • Journal Title: Oncogene Volume: 31 Pages: 2715-24
  • Peer Reviewed
• [Presentation] テモダールの陰翳礼賛から学ぶ悪性神経膠腫の神秘 (2014)
  • Author(s): 夏目敦至
  • Organizer: 第32回日本脳腫瘍学会
  • Place of Presentation: 千葉県浦安市シェラトングランデ
  • Year and Date: 2014-12-02
  • Invited
• [Presentation] 日本におけるTSC標準治療を目指して (2014)
  • Author(s): 夏目敦至
  • Organizer: TSC Days Japan 2014
  • Place of Presentation: 福岡県福岡市ホテル日航
  • Year and Date: 2014-10-25
  • Invited
• [Presentation] 網羅的(エピ)ゲノム解析に基づく治療戦略 (2014)
  • Author(s): 夏目敦至
  • Organizer: 癌治療学会
  • Place of Presentation: 神奈川県横浜市横浜パシフィコ
  • Year and Date: 2014-08-27
  • Invited
• [Presentation] Immunohistochemical analysis-based subclassification of gliomas with integrated genomic and epigenetic profile (2012)
  • Author(s): Natsume A
  • Organizer: Asian Society of Neuro-Oncology
  • Place of Presentation: 台北、台湾(招待講演)
  • Year and Date: 2012-04-21