Analysis of molecular mechanisms involved in the conversion of iPSs into cancer stem cells

• Project/Area Number: 26640079
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Okayama University
• Principal Investigator: Seno Masaharu 岡山大学, 自然科学研究科, 教授 (90243493)
• Co-Investigator(Kenkyū-buntansha): 笠井 智成 岡山大学, 自然科学研究科, 特別契約職員(講師) (30530191) ; 水谷 昭文 岡山大学, 自然科学研究科, 助教 (50598331) ; 工藤 孝幸 岡山大学, 自然科学研究科, 助教 (00346412) ; 村上 宏 岡山大学, 自然科学研究科, 准教授 (90260174) ; 増田 潤子 岡山大学, 自然科学研究科, 特任助教 (20424674)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: iPS細胞 / がん幹細胞 / キナーゼ阻害剤 / 網羅的解析 / 阻害剤

Outline of Final Research Achievements

During the process of cancer stem cells (CSC) generation from induced pluripotent stem cells (iPS), we investigated which signaling pathways were involved in the CSC generation. By screening from various signal inhibitors, we found that the GSK3beta and MEK inhibition promoted CSC generation. In addition, we performed the comprehensive gene expression and epigenetic analysis to find out the intracellular change(s), and nominated candidate genes that might be contributing to the CSC generation.

Research Products

• [Int'l Joint Research] Wayne State University(米国)
• [Journal Article] 球面自己組織化マップを用いたキナーゼパネルアッセイデータのクラスタリング (2016)
  • Author(s): 工藤 孝幸、妹尾昌治
  • Journal Title: CICSJ Bulletin Volume: 34 Issue: 1 Pages: 2
  • DOI: 10.11546/cicsj.34.2
  • NAID: 130005438153
  • ISSN: 0913-3747, 1347-2283
• [Journal Article] A Unique Procedure to Identify Cell Surface Markers Through a Spherical Self-Organizing Map Applied to DNA Microarray Analysis (2016)
  • Author(s): Y. Sugii, T. Kasai, M. Ikeda, A. Vaidyanath, K. Kumon, A. Mizutani, A. Seno, H. Tokutaka, T. Kudoh, M. Seno
  • Journal Title: Biomarkers in Cancer Volume: 8 Pages: 17-23
  • DOI: 10.4137/bic.s33542
  • Peer Reviewed / Open Access
• [Journal Article] A new PDAC mouse model originated from iPSCs-converted pancreatic cancer stem cells (CSCcm) (2016)
  • Author(s): Calle AS, Nair N, Oo AK, Prieto-Vila M, Koga M, Khayrani AC, Hussein M, Hurley L, Vaidyanath A, Seno A, Iwasaki Y, Calle M, Kasai T, Seno M
  • Journal Title: Am J Cancer Res Volume: 6 Pages: 2799-2815
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] iPSC-derived cancer stem cells provide a model of tumor vasculature. (2016)
  • Author(s): Prieto-Vila M, Yan T, Calle AS, Nair N, Hurley L, Kasai T, Kakuta H, Masuda J, Murakami H, Mizutani A, Seno M.
  • Journal Title: Am J Cancer Res Volume: 6 Pages: 1906-1921
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transient Tcf3 Gene Repression by TALE-Transcription Factor Targeting. (2016)
  • Author(s): Masuda J, Kawamoto H, Strober W, Takayama E, Mizutani A, Murakami H, Ikawa T, Kitani A, Maeno N, Shigehiro T, Satoh A, Seno A, Arun V, Kasai T, Fuss IJ, Katsura Y, Seno M
  • Journal Title: Appl Biochem Biotechnol Volume: 180 Issue: 8 Pages: 1559-1573
  • DOI: 10.1007/s12010-016-2187-4
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Characterization of Gene Expression Patterns among Artificially Developed Cancer Stem Cells Using Spherical Self-Organizing Map. (2016)
  • Author(s): Seno A, Kasai T, Ikeda M, Vaidyanath A, Masuda J, Mizutani A, Murakami H, Ishikawa T, Seno M
  • Journal Title: Cancer Inform Volume: 15 Pages: 163-178
• [Journal Article] Sperical Self-organizing Map Detects MYBL1 as Candidate Gene for Triple-Negative Breast Cancer (2015)
  • Author(s): M. Ikeda, K. Kumon, K. Omoto, Y. Sugii, A. Mizutani, A. Vaidyanath, T. Kudoh, T. Kasai, S. Masuda, M. Seno
  • Journal Title: Neuroscience and Biomedical Engineering Volume: 3 Issue: 2 Pages: 94-101
  • DOI: 10.2174/2213385203666151026235610
  • Peer Reviewed / Open Access
• [Journal Article] Insight into Cancer Stem Cell Niche; Lessons from Cancer Stem Cell Models Generated In Vitro (2015)
  • Author(s): MizutaniA, Yan T, Vaidyanath A, Masuda J, Seno A, Kasai T, Murakami H, Seno M
  • Journal Title: Stem Cell Biology and Regenerative Medicine (Springer International Publishing) Volume: 1 Pages: 211-226
  • Peer Reviewed
• [Journal Article] Characterization of cancer stem-like cells derived from mouse induced pluripotent stem cells transformed by tumor-derived extracellular vesicles (2014)
  • Author(s): Yan T, Mizutani A, Chen L, Takaki M, Hiramoto Y, Matsuda S, Shigehiro T, Kasai T, Kudoh T, Murakami H, Masuda J, Hendrix MJ, Strizzi L, Salomon DS, Fu L, Seno M.
  • Journal Title: Journal of Cancer Volume: 5 Issue: 7 Pages: 572-584
  • DOI: 10.7150/jca.8865
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficient drug delivery of Paclitaxel glycoside: a novel solubility gradient encapsulation into liposomes coupled with immunoliposomes preparation. (2014)
  • Author(s): Shigehiro T, Kasai T, Murakami M, Sekhar SC, Tominaga Y, Okada M, Kudoh T, Mizutani A, Murakami H, Salomon DS, Mikuni K, Mandai T, Hamada H, Seno
  • Journal Title: PLoS One Volume: 9 Issue: 9 Pages: e107976-e107976
  • DOI: 10.1371/journal.pone.0107976
  • NAID: 120005477121
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs. (2014)
  • Author(s): El-Aarag BY, Kasai T, Zahran MA, Zakhary NI, Shigehiro T, Sekhar SC, Agwa HS, Mizutani A, Murakami H, Kakuta H, Seno M.
  • Journal Title: International Immunopharmacology Volume: 2 Issue: 2 Pages: 283-92
  • DOI: 10.1016/j.intimp.2014.05.007
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer stem cells converted from pluripotent stem cells and the cancerous niche. (2014)
  • Author(s): Kasai T, Chen L, Mizutani A, Kudoh T, Murakami H, Fu L, Seno M
  • Journal Title: Journal of Stem Cells & Regenerative Medicine Volume: 1 Pages: 2-7
  • Peer Reviewed / Open Access
• [Journal Article] Chlorotoxin-Fc Fusion Inhibits Release of MMP-2 from Pancreatic Cancer Cells. (2014)
  • Author(s): El-Ghlban S, Kasai T, Shigehiro T, Yin HX, Sekhar S, Ida M, Sanchez A, Mizutani A, Kudoh T, Murakami H, Seno M
  • Journal Title: Biomed Res Int. Volume: - Pages: 152659-152659
  • DOI: 10.1155/2014/152659
  • Peer Reviewed / Open Access
• [Journal Article] Mouse induced pluripotent stem cell microenvironment generates epithelial-mesenchymal transition in mouse Lewis lung cancer cells. (2014)
  • Author(s): Chen L, Mizutani A, Kasai T, Yan T, Jin G, Vaidyanath A, El-Aarag BY, Liu Y, Kudoh T, Salomon DS, Fu L, Seno M.
  • Journal Title: American Journal of Cancer Research Volume: 1 Pages: 80-8
  • Peer Reviewed / Open Access
• [Journal Article] Development of 111In-labeled liposomes for vulnerable atherosclerotic plaque imaging (2014)
  • Author(s): Mikako Ogawa, Izumi O. Umeda, Mutsumi Kosugi, Ayumi Kawai, Yuka Hamaya, Misato Takashima, Hongxia Yin, Takayuki Kudoh, Masaharu Seno, Yasuhiro Magata
  • Journal Title: JNucl Med Volume: 55(1) Issue: 1 Pages: 115-120
  • DOI: 10.2967/jnumed.113.123158
  • Peer Reviewed / Open Access
• [Journal Article] ADAM12-cleaved ephrin-A1 contributes to lung metastasis. (2014)
  • Author(s): Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, Duffy SL, Coulthard MG, Boyd A, Maru Y.
  • Journal Title: Oncogene Volume: 未定 Issue: 17 Pages: 2179-90
  • DOI: 10.1038/onc.2013.180
  • Peer Reviewed / Open Access
• [Journal Article] Cancer stem cells maintain a hierarchy of differentiation by creating their niche. (2013)
  • Author(s): Matsuda S, Yan T, Mizutani A, Sota T, Hiramoto Y, Prieto-Vila M, Chen L, Satoh A, Kudoh T, Kasai T, Murakami H, Fu L, Salomon DS, Seno M
  • Journal Title: Int J Cancer Volume: 00 Issue: 1 Pages: 0-0
  • DOI: 10.1002/ijc.28648
  • Peer Reviewed / Open Access
• [Presentation] iPSC derived CSC model with lung metastasis developed in the microenvironment of lung carcinoma. (2016)
  • Author(s): Aung Ko Ko Oo, Tomonori Kasai, Arun Vaidyanath, H.B. Mahmud, Neha Nair, Anna S. Calle, Masaharu Seno.
  • Organizer: ASCB annual meeting 2016
  • Place of Presentation: サンフランシスコ アメリカ
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞から作製するがん幹細胞モデル (2016)
  • Author(s): 五味 真知、星川 健太、岩崎 良章、笠井 智成、妹尾 昌治
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] 胚様体形成させたiPS細胞から誘導するがん幹細胞 (2016)
  • Author(s): 古賀 めぐみ、Anna Sanchez Calle、岩崎 良章、笠井 智成、妹尾 昌治
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] 化学物質によるがん幹細胞誘導性メカニズムの解明 (2016)
  • Author(s): 松本 拓馬、佐々田 沙紀、池田 雅志、Anna Sanchez Calle、笠井 智成、妹尾 昌治
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] TALE-転写因子技術を利用したTcf3遺伝子発現の抑制 (2016)
  • Author(s): 増田 潤子、河本 宏、高山 英次、水谷 昭文、村上 宏、伊川 友活、前野 成実、重廣 司、佐藤 あやの、妹尾 彬正、Arun Vaidyanath、笠井 智成、桂 義元、妹尾 昌治
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Exploration of Target Molecules and Related Pathways Affecting the Conversion of iPSCs into Cancer Stem Cells by Chemical Compounds (2016)
  • Author(s): Takayuki Kudoh, Saki Sasada, Junko Masuda, Masashi Ikeda, Takuma Matsumoto, Anna Sanchez Calle, Neha Nair, Mami Asakura, Tomonari Kasai, Masaharu Seno
  • Organizer: 第５回生命医薬情報学連合大会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-29
• [Presentation] The significance of c-Kit proto-oncogene in iCSC-derived PDAC model (2016)
  • Author(s): Anna Sanchez Calle, Kenta Hoshikawa, Neha Nair, Marta Prieto-Vila, Arun Vaidyanath, Tomonari Kasai, Masaharu Seno
  • Organizer: AACR Annual meeting 2016
  • Place of Presentation: ニューオリンズ アメリカ
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Cancer stem cells as the novel origin of cancer-associated fibroblast-like cells (2016)
  • Author(s): Neha Nair, Arun Vaidyanath, Kenta Hoshikawa, Anna Sanchez Calle, Tomonari Kasai, Masaharu Seno
  • Organizer: AACR Annual meeting 2016
  • Place of Presentation: ニューオリンズ アメリカ
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] 化学物質のがん幹細胞誘導性に関するin vitroにおける簡易評価技術の開発 (2015)
  • Author(s): 佐々田沙紀、星川健太、松本拓馬、Anna Sanchez Calle、Arun Vaidyanath、増田潤子、笠井智成、妹尾昌治
  • Organizer: 日本動物実験代替法学会 第28回大会
  • Place of Presentation: 横浜
  • Year and Date: 2015-12-10
• [Presentation] シグナル伝達阻害剤によるがん幹細胞誘導メカニズムの解析 (2015)
  • Author(s): 佐々田沙紀、星川健太、松本拓馬、Anna Sanchez Calle、水谷昭文、Arun Vaidyanath、増田潤子、笠井智成、妹尾昌治
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] 肝臓がんへ分化するがん幹細胞モデルの作成 (2015)
  • Author(s): 堤愛姫、竹尻崇人、水谷昭文、Arun Vaidyanath、大原利章、岩崎良章、笠井智成、妹尾昌治
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] 乳癌と正常組織を識別する遺伝子セットの網羅的探索 (2015)
  • Author(s): 池田雅志、Arun Vaidyanath、公文一輝、水谷昭文、妹尾彬正、工藤孝幸、笠井智成、妹尾昌治
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] がん幹細胞ニッチでのがん幹細胞自己複製促進 (2015)
  • Author(s): 恩賀咲、平本祐樹、松田修一、村上宏、増田潤子、Arun Vaidyanath、笠井智成、水谷昭文、妹尾昌治
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] マウスiPS細胞由来がん幹細胞におけるダウノルビシンによるp53経路の活性化 (2015)
  • Author(s): 相澤一輝、宗田龍幸、谷口早紀、尾上稜馬、村上宏、増田潤子、Arun Vaidyanath、笠井智成、水谷昭文、妹尾昌治
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] がん幹細胞miPS-LLCcmが形成する微小環境によるNanogタンパク質の局在変化 (2015)
  • Author(s): 公文 一輝、本山 大暉、増田 潤子、Marta Prieto Vila、相澤 一輝、尾上 稜馬、笠井 智成 、村上 宏、水谷 昭文、妹尾 昌治
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] Exploration of Target Molecules Affecting the Conversion of iPS Cells into Cancer Stem Cells Using Chemical Compound Library (2015)
  • Author(s): Takayuki Kudoh, Tomonari Kasai, Saki Sasada, Kenta Hoshikawa, Takuma Matsumoto, Anna Sanchez Calle, Arun Vaidyanath, Masaharu Seno
  • Organizer: CBI学会2015年大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-27
• [Presentation] 多能性幹細胞から作るがん幹細胞モデル (2015)
  • Author(s): 笠井智成、バイディナードアルン、竹尻崇人、村上知加恵、ナイルネハ、サンチェス カレ アンナ、妹尾彬正、水谷昭文、工藤孝幸、陳凌、妹尾昌治
  • Organizer: 第74 回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Acquisition of immortalization prior to malignancy during the miPS-CSC generation (2015)
  • Author(s): Prieto Vila M, Shigehiro T, Sanchez Calle A, Kasai T, Murakami H, Mizutani A, Seno M
  • Organizer: 第74 回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] ニトロアルケンへの-アミノ酸エステルのマイケル付加を鍵反応とする置換ピペラジノン合成法の応用 (2015)
  • Author(s): 鍵本祥子、工藤孝幸、坂倉彰
  • Organizer: 第９５回日本化学会春季年会
  • Place of Presentation: 船橋
  • Year and Date: 2015-03-26 – 2015-03-29
• [Presentation] がん幹細胞ニッチにおけるがん幹細胞の自己複製制御機構の解析 (2014)
  • Author(s): 平本祐樹、渡邉直哉、松田修一、Yan T、Marta P Vila、水谷昭文、村上宏、笠井智成、妹尾昌治
  • Organizer: 第37 回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Tumor derived exosome/microvesicles convert mouse iPS cells to cancer stem-like cells (2014)
  • Author(s): Yan T, Mizutani A, Chen L, Murakami H, Seno M
  • Organizer: 第37 回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] ヒトiPS 細胞から作るがん幹細胞 (2014)
  • Author(s): 笠井智成、水谷昭文、工藤孝幸、佐藤あやの、陳凌、妹尾昌治
  • Organizer: 第37 回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Tumor derived exosomes/microvesicles convert mouse induced pluripotent stem cells to cancer stem cells (2014)
  • Author(s): Yan T, Mizutani A, Chen L, Murakami H, Seno M
  • Organizer: Exosomes & Single cell Analysis Summit
  • Place of Presentation: サンディエゴ アメリカ
  • Year and Date: 2014-09-18 – 2014-09-19
• [Presentation] iPS 細胞から作るがん幹細胞ライブラリー-抗がん剤スクリーニングプラットフォームとして- (2014)
  • Author(s): 笠井智成、本庶仁子、公文一輝、星川健太、竹尻崇人、朝倉真実、水谷昭文、村上宏、妹尾昌治
  • Organizer: 化学療法基盤支援活動第3 回シンポジウム
  • Place of Presentation: 沖縄
  • Year and Date: 2014-05-12
• [Presentation] Cancer stem cells maintain a hierarchy of differentiation by creating their niche (2014)
  • Author(s): Mizutani A, Matsuda S, Yan T, Prieto-Vila M, Chen L, Satoh A, Kasai T, Masuda J, Kudoh T, Murakami H, Fu L, Salomon DS, Seno M
  • Organizer: AACR Annual meeting 2014
  • Place of Presentation: サンディエゴ アメリカ
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Characterization of cancer stem-like cells derived from mouse induced pluripotent stem cells transformed by tumor-derived exosomes/microvesicles (2014)
  • Author(s): Yan T, Masuda J, Mizutani A, Chen L, Shigehiro T, Matsuda S, Kasai T, Kudoh T, Murakami H, Hendrix MJ, Strizzi L, Salomon DS, Seno M
  • Organizer: AACR Annual meeting 2014
  • Place of Presentation: サンディエゴ アメリカ
  • Year and Date: 2014-04-05 – 2014-04-09