The role of epigenetic reprogramming for the acquisition of pluripotency in head and neck cancer stem cells

• Project/Area Number: 16K11255
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: National Hospital Organization, Kyushu Cancer Center
• Principal Investigator: Masuda Muneyuki 独立行政法人国立病院機構(九州がんセンター臨床研究センター), その他部局等, 頭頸科部長 (90284504)
• Research Collaborator: NIKAIDO ITOSHI ; TO SATOSHI ; WAKASAKI TAKAHIRO
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: epigenetics / YAP1 / stemness / carccinogenesis model / mouse / 頭頸部癌 / 発癌モデル / マウス発癌 / epigenetic / マウス発がんモデル / YAP / 多分化能 / 幹細胞 / エピジェネティク

Outline of Final Research Achievements

1.We have developed an ultra-rapid (within 2 weeks) epigenetic mouse carcinogenesis model by the conditional activation of the transcription coactivator YAP1 in the mouse oral epithelium. We also found that YAP1 activation is a strong driver of head and neck squamous cell carcinoma (HNSCC) in both onset and evolution settings through the investigations on human HNSCC tumor samples and cell lines. The more precise epigenetic mechanism is under evaluation. Parts of these results were presented in the symposium of Japan Cancer Association Annual meeting 2019 and are now under review in an English journal.
2. It was also found that YAP1 and SOX2 cooperatively activate transcription of a set of genes and thereby facilitate induction and maintenance of HNSCC stemness. These results are under review in an English journal.

Academic Significance and Societal Importance of the Research Achievements

我々の結果は、現在の遺伝子変異を対象としたprecision medicineの恩恵を受けていない頭頸部癌に対してYAP1を標的としたepigeneticな分子標的治療の可能性を示唆するものであり、頭頸部癌治療に新たな活路を開く可能性がある。また、頭頸部癌（口腔）epigenetic発がんマウスモデルは頭頸部癌研究のみならず、世界的に注目を集めているYAP1阻害剤の開発プラットフォームとして極めて有用と考えられる。

Research Products

• [Journal Article] Prognostic value of programed death ligand-1 and ligand-2 co-expression in salivary gland carcinomas (2019)
  • Author(s): Nakano Takafumi、Takizawa Katsumi、Uezato Azusa、Taguchi Kenichi、Toh Satoshi、Masuda Muneyuki
  • Journal Title: Oral Oncology Volume: 90 Pages: 30-37
  • DOI: 10.1016/j.oraloncology.2019.01.015
  • Peer Reviewed / Open Access
• [Journal Article] Utility of chemoradioselection for the optimization of treatment intensity in advanced hypopharyngeal and laryngeal carcinoma (2017)
  • Author(s): Masuda Muneyuki、Wakasaki Takahiro、Toh Satoshi、Uchida Yoshinori、Rikimaru Hidefumi、Kunitake Naonobu、Higaki Yuichiro
  • Journal Title: Molecular and Clinical Oncology Volume: ７ Pages: 965-970
  • DOI: 10.3892/mco.2017.1466
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low-grade intraductal carcinoma (low-grade cribriform cystadenocarcinoma) with tumor-associated lymphoid proliferation of parotid gland (2017)
  • Author(s): Nishijima T, Yamamoto H, Nakano T, Hatanaka Y, Taguchi KI, Masuda M, Oda Y.
  • Journal Title: Pathol Res Pract Volume: 213 Issue: 6 Pages: 706-709
  • DOI: 10.1016/j.prp.2017.02.019
  • Peer Reviewed / Open Access
• [Journal Article] Transmanubrial Approach for Removing a Head and Neck Tumor Located at the Upper Lateral Mediastinum (2017)
  • Author(s): Masuda Muneyuki、Rikimaru Fumihide、Toh Satoshi、Higaki Yuichiro
  • Journal Title: Biomedicine Hub Volume: 2 Issue: 3 Pages: 7-7
  • DOI: 10.1159/000484685
• [Journal Article] Treatment of Squamous Cell Carcinoma of the Esophagaus Synchronously Associated with Head and Neck Cancer (2017)
  • Author(s): Morita M,Egashira A,Nakai Y,Kagawa M，Sugiyama M,Yoshida D,Ota M,Ikebe M,Masuda M,Inoue Y,Kunitake N,Toh Y
  • Journal Title: in vino Volume: 31 Pages: 909-916
• [Journal Article] Combined transcervical and orbitozygomatic approach for the removal of a nasopharyngeal adenocarcinoma (2016)
  • Author(s): Muneyuki Masuda,Junichi Fukushima,Akiko Fujimura, Hideoki Uryu
  • Journal Title: Auris Nasus Larynx Volume: 43 Issue: 2 Pages: 192-196
  • DOI: 10.1016/j.anl.2015.06.006
  • NAID: 130005250409
  • Peer Reviewed
• [Journal Article] Stress-triggered atavistic reprogramming (STAR) addiction: driving force behind head and neck cancer? (2016)
  • Author(s): Masuda, M. Wakasaki,T. Toh, S.
  • Journal Title: Am J Can Res Volume: 6 Pages: 1149-66
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Transcriptional addiction to YAP1 -the major driving force of oral cancer carcinogenesis and evolution ?- (2019)
  • Author(s): Muneyuki Masuda, Hirofumi Omori, Kuniaki Sato, Kenichi Taguchi, Masashige Bando, Satoshi Toh, Katsuhiko Shirahige, Koshi Mimori, Akira Suzuki
  • Organizer: AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research
  • Int'l Joint Research
• [Presentation] Transcriptional addiction to YAP1 -the major driving force of oral cancer carcinogenesis and evolution ?- (2019)
  • Author(s): Muneyuki Masuda, Hirofumi Omori, Kuniaki Sato, Kenichi Taguchi, Masashige Bando, Satoshi Toh, Katsuhiko Shirahige, Koshi Mimori, Akira Suzuki
  • Organizer: The Hippo Pathway: Signaling, Cancer, and Beyond
  • Int'l Joint Research
• [Presentation] 扁平上皮癌発症におけるHippo経路の役割 (2018)
  • Author(s): 鈴木 聡、西尾美希、大森裕文、藤 庸子、前濱朝彦、青野ゆかり、清野 透、田口健一、益田宗幸、豊國伸哉、田代浩徳、片渕秀隆
  • Organizer: 第77回日本癌学会学術総会
  • Invited
• [Presentation] MOBI-YAP1は頭頸部扁平上皮癌発症の強力なドライバー経路である (2018)
  • Author(s): 大森裕文、西尾美希、佐藤晋彰、田口健一、下野洋平、三森功士、益田宗幸、鈴木 聡
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Utility of chemoradioselection for the optimization of treatment intensity in advanced laryngeal and hypopharyngeal carcinoma (2017)
  • Author(s): Muneyuki Masuda, Takahiro Wakasaki, Satoshi Toh, Naonobu Kunitake, Fumihide Rikimaru, Yuichiro Higaki
  • Organizer: AACR-AHNS Head and Neck Cancer Conference
• [Presentation] 癌研究 UP TO DATE 2017世界の基礎研究の動向 (2017)
  • Author(s): 益田宗幸
  • Organizer: 第41回日本頭頸部癌学会頭頸部癌基礎研究会
• [Presentation] Utility of algorithm-based chemoradioselection for advanced laryngeal and hypopharyngeal carcinoma (2016)
  • Author(s): M.MasudaT.Wakasaki,S.Toh,N.Kunitake,F.Rikimaru,Y.Higaki
  • Organizer: ESMO 2016 Congress
  • Place of Presentation: コペンハーゲン
  • Year and Date: 2016-10-07
  • Int'l Joint Research
• [Book] 頭頸部悪性腫瘍の疑問に答える (2017)
  • Author(s): 益田宗幸
  • Publisher: 東京医学者
• [Book] 頭頸部癌学-診断と治療の最新研究動向- (2017)
  • Author(s): 益田宗幸
  • Total Pages: 615
  • Publisher: 日本臨休