Ｃクラス・Ｍクラスシグネチャーを統合したＥＣＭ分類によるがん分子病態の解明

• Project Area: Conquering cancer through neo-dimensional systems understanding
• Project/Area Number: 16H01574
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Okayama University
• Principal Investigator: 冨田 秀太 岡山大学, 医歯薬学総合研究科, 准教授 (10372111)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2016: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 次世代シークエンサー / 遺伝子変異プロファイル / 遺伝子発現プロファイル / 生体生命情報学 / ゲノム / 肺がん / 遺伝子変異 / コピー数変化 / 分類 / クラスタリング / 癌 / 機械学習 / 人工知能

Outline of Annual Research Achievements

米国の癌ゲノムアトラス（TCGA）プロジェクトや国際癌ゲノムコンソーシアム（ICGC）の大規模ゲノム解析により、遺伝子変異の割合（M-class）とコピー数変異の割合（C-class）はがん種特異的であり、この情報を踏まえて効率的に情報を統合する事の重要性が明らかになってきた。本研究課題では、網羅的遺伝子発現プロファイル情報（E-class）、C-class（CNV：コピー数変異）とM-class（Mutation：遺伝子変異）の情報を統合したECM分類手法を開発し、新規サブクラスに基づくがん分子病態の解明と、ドラッグリポジショニングを含む治療薬最適化アルゴリズムを患者モデルで検証することを目的としている。研究期間中、がん死亡原因の１位である難治性固形腫瘍の肺がんを対象に、M-classとC-classの割合が50％ずつであり、分子標的薬の開発が先行している肺腺がん（LUAD）を用いて遺伝子変異情報を主体にしたMEC/MCEモデルの構築手法を検討した。
当該研究では、KRAS陽性LUADにおいては、MEK阻害剤に対する耐性獲得メカニズムが上皮間葉転換（Epithelial to mesenchymal transition; EMT）を指標にして異なること、また、非小細胞肺癌細胞株34株を用いた解析により、EMTとmiR-200cおよびLIN28Bの発現パターンが相関することを示しており、M-classとEMTに関連するE-classの関連性を明らかにしてきた。
当該年度の検討では、第3世代EGFR阻害剤に対する耐性獲得メカニズムの解明を目的に、RNA-Seqを用いたKinase関連遺伝子発現プロファイルの解析を実施するとともに、リン酸化アレイの解析からMETやNRAS遺伝子の増幅の増幅を見出し、MEK阻害剤と第3世代EGFR阻害剤との併用療法を検討した。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers (2018)
  • Author(s): Kotani Hiroshi、Adachi Yuta、Kitai Hidenori、Tomida Shuta、Bando Hideaki、Faber Anthony C.、Yoshino Takayuki、Voon Dominic C.、Yano Seiji、Ebi Hiromichi
  • Journal Title: Oncogene Volume: 37 Issue: 13 Pages: 1775-1787
  • DOI: 10.1038/s41388-017-0035-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib (2018)
  • Author(s): Ninomiya Kiichiro、Ohashi Kadoaki、Makimoto Go、Tomida Shuta、Higo Hisao、Kayatani Hiroe、Ninomiya Takashi、Kubo Toshio、Ichihara Eiki、Hotta Katsuyuki、Tabata Masahiro、Maeda Yoshinobu、Kiura Katsuyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1955-1955
  • DOI: 10.1038/s41598-018-20326-z
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma (2018)
  • Author(s): Sato Hiroki、Sakaguchi Masakiyo、Yamamoto Hiromasa、Tomida Shuta、Aoe Keisuke、Shien Kazuhiko、Yoshioka Takahiro、Namba Kei、Torigoe Hidejiro、Soh Junichi、Tsukuda Kazunori、Tao Hiroyuki、Okabe Kazunori、Miyoshi Shinichiro、Pass Harvey I.、Toyooka Shinichi
  • Journal Title: Oncogenesis Volume: 7 Issue: 1 Pages: 11-11
  • DOI: 10.1038/s41389-017-0017-3
  • Peer Reviewed / Open Access
• [Journal Article] PIK3R1Met326Ile germline mutation correlates with cysteine-rich protein 61 expression and poor prognosis in glioblastoma (2017)
  • Author(s): Otani Yoshihiro、Ishida Joji、Kurozumi Kazuhiko、Oka Tetsuo、Shimizu Toshihiko、Tomita Yusuke、Hattori Yasuhiko、Uneda Atsuhito、Matsumoto Yuji、Michiue Hiroyuki、Tomida Shuta、Matsubara Takehiro、Ichikawa Tomotsugu、Date Isao
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 7391-7391
  • DOI: 10.1038/s41598-017-07745-0
  • Peer Reviewed / Open Access
• [Journal Article] Tumor Immune Microenvironment and Nivolumab Efficacy in EGFR Mutation-Positive Non-Small Cell Lung Cancer Based on T790M Status After Disease Progression During EGFR-TKI Treatment (2017)
  • Author(s): K. Haratani, H. Hayashi*, T. Tanaka, H. Kaneda, Y. Togashi, K. Sakai, K. Hayashi, S. Tomida, Y. Chiba, K. Yonesaka, Y. Nonagase, T. Takahama, J. Tanizaki, K. Tanaka, T. Yoshida, K. Tanimura, M. Takeda, H. Yoshioka, T. Ishida, T. Mitsudomi, K. Nishio and K. Nakagawa
  • Journal Title: Annals of Oncology Volume: in press Issue: 7 Pages: 1532-1539
  • DOI: 10.1093/annonc/mdx183
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system. (2017)
  • Author(s): Suzawa K, Yamamoto H, Ohashi K, Hashida S, Tomida S, Kubo T, Maki Y, Soh J, Tsukuda K, Kiura K, Miyoshi S, Toyooka S.
  • Journal Title: Oncol Rep. Volume: 37 Issue: 5 Pages: 3100-3106
  • DOI: 10.3892/or.2017.5567
  • Peer Reviewed
• [Journal Article] The H3K27 demethylase, Utx, regulates adipogenesis in a differentiation stage-dependent manner. (2017)
  • Author(s): Ota K, Tong KI, Goto K, Tomida S, Komuro A, Wang Z, Nishio K, Okada H.
  • Journal Title: PLoS One. Volume: 12 Issue: 3 Pages: e0173713-e0173713
  • DOI: 10.1371/journal.pone.0173713
  • Peer Reviewed / Open Access
• [Journal Article] Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer. (2017)
  • Author(s): Takeda T, Yamamoto H, Kanzaki H, Suzawa K, Yoshioka T, Tomida S, Cui X, Murali R, Namba K, Sato H, Torigoe H, Watanabe M, Shien K, Soh J, Asano H, Tsukuda K, Kitamura Y, Miyoshi S, Sendo T, Toyooka S.
  • Journal Title: PLoS One. Volume: 12 Issue: 2 Pages: e0171356-e0171356
  • DOI: 10.1371/journal.pone.0171356
  • Peer Reviewed / Open Access
• [Journal Article] Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features. (2017)
  • Author(s): Sato H, Shien K, Tomida S, Okayasu K, Suzawa K, Hashida S, Torigoe H, Watanabe M, Yamamoto H, Soh J, Asano H, Tsukuda K, Miyoshi S, Toyooka S.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 40847-40847
  • DOI: 10.1038/srep40847
  • Peer Reviewed / Open Access
• [Journal Article] Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies. (2017)
  • Author(s): Suzawa K, Shien K, Peng H, Sakaguchi M, Watanabe M, Hashida S, Maki Y, Yamamoto H, Tomida S, Soh J, Asano H, Tsukuda K, Nasu Y, Kumon H, Miyoshi S, Toyooka S.
  • Journal Title: Anticancer Res. Volume: 37 Pages: 301-307
  • Peer Reviewed
• [Journal Article] Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway. (2016)
  • Author(s): Ohtsuka T, Sakaguchi M, Yamamoto H, Tomida S, Takata K, Shien K, Hashida S, Miyata-Takata T, Watanabe M, Suzawa K, Soh J, Youyi C, Sato H, Namba K, Torigoe H, Tsukuda K, Yoshino T, Miyoshi S, Toyooka S.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 39557-39557
  • DOI: 10.1038/srep39557
  • Peer Reviewed / Open Access
• [Journal Article] Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. (2016)
  • Author(s): Saho S, Satoh H, Kondo E, Inoue Y, Yamauchi A, Murata H, Kinoshita R, Yamamoto KI, Futami J, Putranto EW, Ruma IM, Sumardika IW, Youyi C, Suzawa K, Yamamoto H, Soh J, Tomida S, Sakaguchi Y, Saito K, Iioka H, Huh NH, Toyooka S, Sakaguchi M.
  • Journal Title: Cancer Microenviron. Volume: 9 Issue: 2-3 Pages: 93-105
  • DOI: 10.1007/s12307-016-0185-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MEK inhibitors against MET-amplified non-small cell lung cancer. (2016)
  • Author(s): Chiba M, Togashi Y, Tomida S, Mizuuchi H, Nakamura Y, Banno E, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Mitsudomi T, Nishio K.
  • Journal Title: Int J Oncol. Volume: 49 Issue: 6 Pages: 2236-2244
  • DOI: 10.3892/ijo.2016.3736
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC. (2016)
  • Author(s): Nakamura Y, Togashi Y, Nakahara H, Tomida S, Banno E, Terashima M, Hayashi H, de Velasco MA, Sakai K, Fujita Y, Okegawa T, Nutahara K, Hamada S, Nishio K.
  • Journal Title: Mol Cancer Ther. Volume: 15 Issue: 8 Pages: 1988-1997
  • DOI: 10.1158/1535-7163.mct-15-0737
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer. (2016)
  • Author(s): Kitai H, Ebi H, Tomida S, Floros KV, Kotani H, Adachi Y, Oizumi S, Nishimura M, Faber AC, Yano S.
  • Journal Title: Cancer Discov. Volume: 6 Issue: 7 Pages: 754-769
  • DOI: 10.1158/2159-8290.cd-15-1377
  • Peer Reviewed
• [Presentation] 分子バーコード技術を用いた低頻度多重変異の同定 (2017)
  • Author(s): 難波圭、冨田秀太、枝園和彦、山本寛斉、宗淳一、佃和憲、豊岡伸一
  • Organizer: 日本癌学会学術総会