Bayesian modeling for analyzing, integrating and understanding of intracellular metabolic shifts

• Project/Area Number: 15H05325
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Life / Health / Medical informatics
• Research Institution: Nagoya University
• Principal Investigator: Shimamura Teppei 名古屋大学, 医学系研究科, 特任准教授 (00623943)
• Research Collaborator: OSAWA Tsuyoshi
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000); Fiscal Year 2018: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
• Keywords: 代謝ネットワーク / システム生物学 / ネットワーク解析 / 代謝シフト / マルチオミクス / 生体生命情報学 / バイオインフォマティクス

Outline of Final Research Achievements

In this research, we developed a integrated Bayesian approach for multi omics data in order to analyze, integrate, and understand intracellular metabolic shifts by estimating hierarchical cross-sectional metabolic flow networks with high prediction accuracy. We tried to apply to drug elucidation of energy metabolism in metabolic disorders and cancer, disease diagnosis, and search for various disease markers. As a result, we obtained the following results. (1) We clarified the metabolic shift for cancer growth in harsh environments, and (2) we discovered that the metabolic regulatory protein corresponding to the malignant transformation of the tumor in the acidic environment contributes.

Academic Significance and Societal Importance of the Research Achievements

本研究課題は、本来多階層である情報を一部の分子のみ、あるいは１つの階層のみに着目して解析することで生じる情報損失を回避し、従来型アプローチの限界を克服することを目的としている。このための数理モデルの構築、推測、評価に関する一連の研究を確固たる理論基盤の上で実施することが本研究課題の学術的特色である。
本研究が完遂されることで、分子生物学的アプローチだけでこれまで得ることの出来なかった新しい知見が得られる可能性は極めて高く、多因子疾患の分子病態解明や新規薬剤標的候補の合理的スクリーニングなど社会的ニーズの高い課題の解決に寄与することが期待されるため、本研究課題を推進する意義は大きい。

Research Products

• [Journal Article] ENIGMA: An Enterotype-Like Unigram Mixture Model for Microbial Association Analysis. (2019)
  • Author(s): Abe K, Hirayama H, Ohno K, Shimamura T.
  • Journal Title: BMC Genomics Volume: 20(Suppl 2) Issue: S2 Pages: 191-191
  • DOI: 10.1186/s12864-019-5476-9
  • Peer Reviewed / Open Access
• [Journal Article] Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis (2019)
  • Author(s): Kidoya H, Muramatsu F, Shimamura T, Jia W, Satoh T, Hayashi Y, Naito H, Kunisaki Y, Arai F, Seki M, Suzuki Y, Osawa T, Akira S., Takakura N.
  • Journal Title: Nature Commun, Volume: 10 Issue: 1 Pages: 1072-1072
  • DOI: 10.1038/s41467-019-09028-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Network of Networks Approach for Modeling Interconnected Brain Tissue-Specific Networks. (2019)
  • Author(s): Kawakubo H, Matsui Y, Kushima I, Ozaki N, Shimamura T.
  • Journal Title: Bioinformatics Volume: - Issue: 17 Pages: 1-10
  • DOI: 10.1093/bioinformatics/btz032
  • Peer Reviewed / Open Access
• [Journal Article] GIMLET: Identifying biological modulators in context-specific gene regulation using local energy statistics. (2018)
  • Author(s): Shimamura T, Matsui Y, Kajino T, Ito S, Takahashi T, Miyano S.
  • Journal Title: Lecture Notes in Bioinformatics Volume: 10834 Pages: 115-123
  • DOI: 10.1101/349928
  • Peer Reviewed
• [Journal Article] Tumor subclonal progression model for cancer hallmark acquisition. (2018)
  • Author(s): Matsui Y, Miyano S, Shimamura T.
  • Journal Title: Lecture Notes in Bioinformatics Volume: 10834 Pages: 124-137
  • DOI: 10.1101/149252
  • Peer Reviewed
• [Journal Article] Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. (2018)
  • Author(s): Kushima I, (27名中略）, Hashimoto R,(80名中29番目) , et al.
  • Journal Title: Cell Rep Volume: 24(11) Issue: 11 Pages: 2838-2856
  • DOI: 10.1016/j.celrep.2018.08.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A latent allocation model for the analysis of microbial composition and disease (2018)
  • Author(s): Abe K, Hirayama H, Ohno K, Shimamura T.
  • Journal Title: BMC Bioinformatics Volume: 19(Suppl 19) Issue: S19 Pages: 519-519
  • DOI: 10.1186/s12859-018-2530-6
  • Peer Reviewed / Open Access
• [Journal Article] A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer (2018)
  • Author(s): Saito T, Niida A, Uchi R, Hirata H, Kodama M, Okimoto T, Murakami K, Suzuki Y, Ogawa S, Miyano S, Mimori K, et al.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2884-2884
  • DOI: 10.1038/s41467-018-05226-0
  • NAID: 120006551763
  • Peer Reviewed / Open Access
• [Journal Article] hibition controls aggressive prostate tumors deficient in Y-linked histone demethylase KDM5D. (2018)
  • Author(s): Komura K、Yoshikawa Y, Shimamura T, Chakraborty G, Gerke TA, Hinohara K, Chadalavada K, Jeong SH, Armenia J, Du SY, Mazzu YZ, Taniguchi K, Ibuki N, Meyer CA, Nanjangud GJ, Inamoto T, Lee GM, Mucci LA, Azuma H, Sweeney CJ, Kantoff PW.
  • Journal Title: Journal of Clinical Investigation Volume: 128(7) Issue: 7 Pages: 2979-95
  • DOI: 10.1172/jci96769
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Cardiomyocyte-Fated Progenitors from Human-Induced Pluripotent Stem Cells Marked with CD82 (2018)
  • Author(s): Takeda Masafumi、Kanki Yasuharu、Masumoto Hidetoshi、Funakoshi Shunsuke、Hatani Takeshi、Fukushima Hiroyuki、Izumi-Taguchi Akashi、Matsui Yusuke、Shimamura Teppei、Yoshida Yoshinori、Yamashita Jun K.
  • Journal Title: Cell Reports Volume: 22 Issue: 2 Pages: 546-556
  • DOI: 10.1016/j.celrep.2017.12.057
  • NAID: 120006460050
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma (2018)
  • Author(s): Isobe T, Seki M, Yoshida K, Sekiguchi M, Shiozawa Y, Shiraishi Y,..., Kataoka K, Sato Y, Kawai T, Chiba K, Tanaka H, Shimamura T, Kato M, Iguchi A, Hama A, Taguchi T, Akiyama M, Fujimura J, Inoue A, Ito T, Deguchi T, Kiyotani C, Iehara T, Hosoi H, Oka A, Sanada M, Tanaka Y, Hata K, Miyano S, Ogawa S, Takita J
  • Journal Title: Cancer Res Volume: 78(4) Issue: 4 Pages: 865-876
  • DOI: 10.1158/0008-5472.can-17-2581
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adaptive NetworkProfiler for Identifying Cancer Characteristic-Specific Gene Regulatory Networks (2018)
  • Author(s): Park H, Shimamura T, Imoto S, Miyano S
  • Journal Title: J Comput Biol Volume: 25(2) Issue: 2 Pages: 130-145
  • DOI: 10.1089/cmb.2017.0120
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ER Stress Signaling Promotes the Survival of Cancer “Persister Cells” Tolerant to EGFR Tyrosine Kinase Inhibitors (2017)
  • Author(s): Terai Hideki、Kitajima Shunsuke、Potter Danielle S.、Matsui Yusuke、et al.
  • Journal Title: Cancer Research Volume: 78 Issue: 4 Pages: 1044-1057
  • DOI: 10.1158/0008-5472.can-17-1904
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comprehensive genetic analysis of donor cell derived leukemia with KMT2A rearrangement. (2017)
  • Author(s): Taniguchi R, Muramatsu H, Okuno Y, Suzuki K, Obu S, Nakatochi M, Shimamura T, Takahashi Y, Horikoshi Y, Watanabe K, Kojima S.
  • Journal Title: Pediatr Blood Cancer Volume: 65(2) Issue: 2
  • DOI: 10.1002/pbc.26823
  • Peer Reviewed
• [Journal Article] Japanese genome-wide association study identifies a significant colorectal cancer susceptibility locus at chromosome 10p14. (2017)
  • Author(s): Takahashi Y, Sugimachi K, Yamamoto K, Niida A, Shimamura T, Sato T, Watanabe M, Tanaka J, Kudo S, Sugihara K, Hase K, Kusunoki M, Yamada K, Shimada Y, Moriya Y, Suzuki Y, Miyano S, Mori M, Mimori K
  • Journal Title: Cancer Sci. Volume: 108(11) Issue: 11 Pages: 2239-2247
  • DOI: 10.1111/cas.13391
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PRC2-mediated transcriptomic alterations at the embryonic stage govern tumorigenesis and clinical outcome in MYCN-driven neuroblastoma. (2017)
  • Author(s): Tsubota S, Kishida S, Shimamura T, Ohira M, Yamashita S, Cao D, Kiyonari S, Ushijima T, Kadomatsu K.
  • Journal Title: Cancer Res Volume: 77(19) Pages: 5259-5271
  • Peer Reviewed
• [Journal Article] Prognostic relevance of genetic alterations in diffuse lower-grade gliomas (2017)
  • Author(s): Aoki Kosuke、Nakamura Hideo、Suzuki Hiromichi et al.
  • Journal Title: Neuro-Oncology Volume: 20 Issue: 1 Pages: 66-77
  • DOI: 10.1093/neuonc/nox132
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. (2017)
  • Author(s): Seki M, Kimura S, Isobe T, Yoshida K, (13 authors), Masuda K, Kawamoto H, Ohki K, Kato M, Arakawa Y, Koh K, Hanada R, Moritake H, Akiyama M, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi Y, Takagi M, Manabe A, Ohara A, Horibe K, Sanada M, Iwama A, Mano H, Miyano S, Ogawa S, Takita J
  • Journal Title: Nature Genetics Volume: 49 Issue: 8 Pages: 1274-1281
  • DOI: 10.1038/ng.3900
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long Noncoding RNA JHDM1D-AS1 Promotes Tumor Growth by Regulating Angiogenesis in Response to Nutrient Starvation (2017)
  • Author(s): Kondo A, Nonaka A, Shimamura T, Yamamoto S, Yoshida T, Kodama T, Aburatani H, Osawa T
  • Journal Title: Molecular and Cellular Biology Volume: 37 Issue: 18
  • DOI: 10.1128/mcb.00125-17
  • Peer Reviewed / Open Access
• [Journal Article] phyC: Clustering cancer evolutionary trees. (2017)
  • Author(s): Matsui Y, Niida A, Uchi R, Mimori K, Miyano S, Shimamura T:
  • Journal Title: PLoS Comput Biol. Volume: 13(5) Issue: 5 Pages: 1005509-1005509
  • DOI: 10.1371/journal.pcbi.1005509
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamically and epigenetically coordinated GATA/ETS/SOX transcription is indispensable for endothelial cell differentiation (2017)
  • Author(s): Kanki Y, Nakaki R, Shimamura T, Matsunaga T, Yamamizu K, Katayama S, Suehiro JI, Osawa T, Aburatani H, Kodama T, Wada Y, Yamashita JK, Minami T.
  • Journal Title: Nucleic Acids Research Volume: 印刷中 Issue: 8 Pages: 4344-4358
  • DOI: 10.1093/nar/gkx159
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells (2017)
  • Author(s): Tominaga K, Shimamura T, Kimura N, Murayama T, Matsubara D, Kanauchi H, Niida A, Shimizu S, Nishioka K, Tsuji EI, Yano M, Sugano S, Shimono Y, Ishii H, Saya H, Mori M, Akashi K, Tada KI, Ogawa T, Tojo A, Miyano S, Gotoh N
  • Journal Title: Oncogene Volume: 36(9) Issue: 9 Pages: 1276-1286
  • DOI: 10.1038/onc.2016.293
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular Acidic pH Activates the Sterol Regulatory Element-binding Protein 2 to Promote Tumor Progression (2017)
  • Author(s): Kondo A, Yamamoto S, Nakaki R, Shimamura T, Hamakubo T, Sakai J, Kodama T, Yoshida T, Aburatani H and Osawa T
  • Journal Title: Cell Reports Volume: 18 Issue: 9 Pages: 2228-2242
  • DOI: 10.1016/j.celrep.2017.02.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Detection of differential distributions of methylation patterns (2016)
  • Author(s): Matsui Y, Mizuta M, Miyano S, Shimamura T
  • Journal Title: Bioinformatics Volume: 印刷中 Issue: 15 Pages: 1-8
  • DOI: 10.1093/bioinformatics/btw138
  • Peer Reviewed / Open Access
• [Journal Article] NECAB3 Promotes Activation of Hypoxia-inducible factor-1 during Normoxia and Enhances Tumourigenicity of Cancer Cells (2016)
  • Author(s): 1.Nakaoka HJ, Hara T, Yoshino S, Kanamori A, Matsui Y, Shimamura T, Sato H, Murakami Y, Seiki M, Sakamoto T
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 22784-22784
  • DOI: 10.1038/srep22784
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Integrated Multiregional Analysis Proposing a New Model of Colorectal Cancer Evolution. (2016)
  • Author(s): R. Uchi (他40名, 山本36番目)
  • Journal Title: PLoS Genetics Volume: 12 Issue: 2 Pages: 1-24
  • DOI: 10.1371/journal.pgen.1005778
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aberrant Methylation of FOXE1 Contributes to a Poor Prognosis for Patients with Colorectal Cancer. (2016)
  • Author(s): Sugimachi K, Matsumura T, Shimamura T, Hirata H, Uchi R, Ueda M, Sakimura S, Iguchi T, Eguchi H, Masuda T, Morita K, Takenaka K, Maehara Y, Mori M, Mimori K.
  • Journal Title: Ann Surg Oncol. Volume: 23(12) Issue: 12 Pages: 3948-3955
  • DOI: 10.1245/s10434-016-5289-x
  • Peer Reviewed / Open Access
• [Presentation] Sparse Regression Modeling of Drug Response with A Localized Estimation Framework (2018)
  • Author(s): 島村徹平
  • Organizer: The Pacific Symposium on Biocomputing (PSB) 2018
  • Int'l Joint Research
• [Presentation] データサイエンスとの連携・融合による生命科学研究の新時代 (2018)
  • Author(s): 島村徹平
  • Organizer: 第61回日本神経化学会大会
  • Invited
• [Presentation] バイオインフォマティクスにおけるスパースモデリング (2018)
  • Author(s): 島村徹平
  • Organizer: 日本行動計量学会 第46回大会
  • Invited
• [Presentation] がん微小環境における細胞間相互作用のモデリング (2018)
  • Author(s): 島村徹平
  • Organizer: 2018年度統計関連学会連合大会
  • Invited
• [Presentation] 疾患メタゲノム解析のためのベイズモデリング (2018)
  • Author(s): 島村徹平
  • Organizer: 第7回生命医薬情報学連合大会(IIBMP2018)
  • Invited
• [Presentation] 腫瘍内不均一性の一細胞トランスクリプトーム解析のためのバイオインフォマティクス (2018)
  • Author(s): 島村徹平
  • Organizer: 第77回日本癌学会学術総会
  • Invited
• [Presentation] がん免疫システムの時間・空間・個体間多様性を読み解くデータサイエンス (2018)
  • Author(s): 島村徹平
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] GIMLET: Identifying Biological Modulators in Context-Specific Gene Regulation Using Local Energy Statistics (2017)
  • Author(s): 島村徹平
  • Organizer: CIBB2017(Computational Intelligence methods for Bioinformatics and Biostatistics)
  • Int'l Joint Research
• [Presentation] 生命科学におけるビッグデータ駆動型科学の実践と将来 (2017)
  • Author(s): 島村徹平
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Invited
• [Presentation] Sparse Regression Modeling of Drug Response with A Localized Estimation Framework (2017)
  • Author(s): 島村徹平
  • Organizer: ISMB/ECCB2017(Intelligent Systems for Molecular Biology and the 16TH European Conference on Computational Biology)
  • Int'l Joint Research
• [Presentation] マルチオミックス情報に基づくがんのモジュレーター因子の網羅的探索 (2016)
  • Author(s): 島村徹平
  • Organizer: 第５回生命医薬情報学連合大会
  • Invited
• [Presentation] システム生物学的アプローチに基づくオミックス統合解析 (2016)
  • Author(s): 島村徹平
  • Organizer: 第３９回日本分子生物学会年会
  • Invited
• [Presentation] がんの俯瞰的理解のための統合的統計モデリング (2015)
  • Author(s): 島村徹平
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Invited