数理的統計的解析による難治性癌幹細胞システムの解明と創薬応用

• Project Area: Integrative Systems Understanding of Cancer for Advanced Diagnosis, Therapy and Prevention
• Project/Area Number: 25134711
• 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: Osaka University
• Principal Investigator: 石井 秀始 大阪大学, 医学(系)研究科(研究院), 特任教授(常勤) (10280736)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 癌 / トランスレーショナルリサーチ / 発現制御 / 薬学 / バイオテクノロジー

Outline of Annual Research Achievements

前年度に引き続き、数理的統計的解析の手法を活用して難治性消化器癌幹細胞システムの多様性を解明し、出口戦略として創薬outputを導出に向けて研究した。本研究では難治性消化器癌幹細胞（膵癌・転移性大腸癌）を対象にして、最新の生体ｲﾒｰｼﾞﾝｸﾞ技術で「多様性」細胞を捕捉した材料を用いて、抗癌剤暴露後に残存する寡少細胞群の個々細胞ﾚﾍﾞﾙの時系列遺伝子発現情報を最先端ｼｰｸｴﾝｽ技術で取得しﾋﾄｹﾞﾉﾑ情報を参照してｽｰﾊﾟｰｺﾝﾋﾟｭｰﾀｰを用いた数理的・情報科学的方法論を適用した。【生物研究】（１）細胞間多様性：癌幹細胞を生体ｲﾒｰｼﾞﾝｸﾞ（GFP-Degron)により細胞を1細胞ﾚﾍﾞﾙまで分離、高性能力取装置(AriaII,阪大）で収集。(2)細胞内多様性:多中発現量遺伝子は次世代ｼｰｸｴﾝｽにより、また小発現量遺伝子はHiCEP法(polyA+）により、mRNAおよび非コードRNAを解析。(３)時系列データ（細胞実験）【数理解析】(1)癌幹細胞細胞間多様性、(2)細胞内多様性(3)サブネットワークを抽出。【POC(proof-of-concept)確認】(１)臨床データ。(２)試験管内実験。これらを基にして癌幹細胞に特徴的なオートミックス解析を行い、エピゲノムと転写、転写と代謝を結びつけて数理的統計的なエビデンスに基づく創薬の創出に向けて基盤を構築した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. (2014)
  • Author(s): Yoshioka Y, Kosaka N, Konishi Y, Ohta H, Okamoto H, Sonoda H, Nonaka R, Yamamoto H, Ishii H, Mori M, Furuta K, Nakajima T, Hayashi H, Sugisaki H, Higashimoto H, Kato T, Takeshita F, Ochiya T.
  • Journal Title: Nat. Commun. Volume: 5 Pages: 3591-3591
  • DOI: 10.1038/ncomms4591
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer. (2014)
  • Author(s): Lovat, F., Ishii, H., Schiappacassi, M., Fassan, M., Barbareschi, M., Galligioni, E., Gasparini, P., Baldassarre, G., Croce, CM., Vecchione, A.
  • Journal Title: Oncotarget Volume: 5 Pages: 970-977
  • Peer Reviewed
• [Journal Article] CD10 as a novel marker of therapeutic resistance and cancer stem cells in head and neck squamous cell carcinoma. (2014)
  • Author(s): Fukusumi T, Ishii H, Konno M, Yasui T, Nakahara S, Takenaka Y, Yamamoto Y, Nishikawa S, Kano Y, Ogawa H, Hasegawa S, Hamabe A, Haraguchi N, Doki Y, Mori M, Inohara H.
  • Journal Title: Br. J. Cancer Volume: 111(3) Pages: 506-514
  • DOI: 10.1038/bjc.2014.289
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer. (2014)
  • Author(s): Hasegawa S, Eguchi H, Nagano H, Konno M, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Nishida N, Koseki J, Nishimura T, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H.
  • Journal Title: B.r J. Cancer Volume: 111 Pages: 1572-1580
  • DOI: 10.1038/bjc.2014.454
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase-E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis. (2014)
  • Author(s): Hamabe, A. Yamamoto, H. Konno, M. Uemura, M. Nishimura, J. Hata, T. Takemasa, I. Mizushima, T. Nishida, N. Kawamoto, K. Koseki, J. Doki, Y. Mori, M. Ishii, H.
  • Journal Title: Cancer Sci. Volume: 105 Pages: 1100-1108
  • DOI: 10.1111/cas.12487
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. (2014)
  • Author(s): Hamabe, A. Konno, M. Tanuma, N. Shima, H. Tsunekuni, K. Kawamoto, K. Nishida, N. Koseki, J. Mimori, K. Gotoh, N. Yamamoto, H. Doki, Y. Mori, M. Ishii, H.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Pages: 15526-15531
  • DOI: 10.1073/pnas.1407717111
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SSEA-3 as a novel amplifying cancer cell surface marker in colorectal cancers. (2013)
  • Author(s): Suzuki, Y., Haraguchi, N., Takahashi, H., Uemura, M., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Ishii, H., Doki, Y., Mori, M., Yamamoto, H.
  • Journal Title: Int. J. Oncol Volume: 42 Pages: 161-167
  • DOI: 10.3892/ijo.2012.1713
  • Peer Reviewed
• [Journal Article] The rs6983267 SNP Is Associated with MYC Transcription Efficiency Which Promotes Progression and Worsens Prognosis of Colorectal Cancer. (2013)
  • Author(s): Takatsuno Y
  • Journal Title: Ann Surg Oncol. Volume: 20 Pages: 1395-1402
  • DOI: 10.1245/s10434-012-2657-z
  • Peer Reviewed
• [Journal Article] Jumonji/Arid1b (Jarid1b) protein modulates human esophageal cancer cell growth (2013)
  • Author(s): Kano, Y., Konno, M., Ohta, K., Haraguchi, N., Nishikawa, S., Kagawa, Y., Hamabe, A., Hasegawa, S., Ogawa, H., Fukusumi, T., Noguchi, Y., Ozaki, M., Kudo, T., Sakai, D., Satoh, T., Ishii, M., Mizohata, E., Inoue, T., Mori, M., Doki, Y., Ishii, H.
  • Journal Title: Molecular and Clinical Oncology Volume: 1 Pages: 753-757
  • DOI: 10.3892/mco.2013.127
  • Peer Reviewed
• [Journal Article] The REV7 subunit of DNA polymerase zeta is essential for primordial germ cell maintenance in the mouse. (2013)
  • Author(s): Watanabe, N., Mii, S., Asai, N., Asai, M., Niimi, K., Ushida, K., Kato, T., Enomoto, A., Ishii, H., Takahashi, M., Murakumo, Y.
  • Journal Title: J Biol Chem. Volume: 288 Pages: 10459-10471
  • DOI: 10.1074/jbc.m112.421966
  • Peer Reviewed
• [Journal Article] CD49f-positive cell population efficiently enriches colon cancer-initiating cells. (2013)
  • Author(s): Haraguchi, N., Ishii, H., Mimori, K., Ohta, K., Uemura, M., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Yamamoto, H., Doki, Y., Mori, M.
  • Journal Title: Int. J. Oncol. Volume: 43 Pages: 425-430
  • Peer Reviewed
• [Journal Article] Adipose-derived mesenchymal stem cells and regenerative medicine (2013)
  • Author(s): Konno, M., Hamabe, A., Hasegawa, S., Ogawa, H., Fukusumi, T., Nishikawa, S., Ohta, K., Kano, Y., Ozaki, M., Noguchi, Y., Sakai, D., Kudoh, T., Kawamoto, K., Eguchi, H., Satoh, T., Tanemura, M., Nagano, H., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Dev Growth Differ Volume: 55 Pages: 309-18
  • DOI: 10.1111/dgd.12049
  • NAID: 40019735006
  • Peer Reviewed
• [Presentation] Innovative drug discovery for intractable cancer stem cells (2014)
  • Author(s): 石井秀始
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 創薬標的としての癌幹細胞エピゲノム代謝 (2014)
  • Author(s): 石井秀始
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 難治性消化器癌に対する革新的治療法 (2014)
  • Author(s): 石井秀始、土岐祐一郎、森正樹
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 難治性消化器癌に対する革新的医療技術の創出 (2013)
  • Author(s): 石井秀始、土岐 祐一郎、森 正樹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] 癌幹細胞研究の現状と展望 (2013)
  • Author(s): 石井秀始
  • Organizer: 第23回日本サイトメトリー学会学術集会
  • Place of Presentation: 日本医科大学橘桜会館（東京都）