Elucidation of anaplastic thyroid cancer formation and development of novel treatment strategy

• Project/Area Number: 19K21352
• Project/Area Number (Other): 18H06260 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0906:Surgery related to the biological and sensory functions and related fields
• Research Institution: Gifu University
• Principal Investigator: Shibata Hirofumi 岐阜大学, 医学部附属病院, 講師 (20610421)
• Project Period (FY): 2018-08-24 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 甲状腺未分化がん / 多能性関連遺伝子 / 脱分化 / 未分化転化 / 甲状腺がん / 未分化がん / MAPキナーゼ / エピゲノム / 甲状腺癌 / 未分化癌

Outline of Research at the Start

がんは発生元の細胞形質を残した高分化がんから、発生元の細胞形質を完全に喪失し幼弱な状態に近くなった未分化がんまで、種々の分化度をもつ。臨床的に最も悪性度の高いがんの一つである甲状腺未分化がんも非常に幼弱な細胞集団から構成されている。過去の報告より、ある種の未分化がんではES細胞、iPS細胞などのいわゆる多能性細胞と近い性質をもつことが報告されている。甲状腺未分化がんにおいても、これら多能性遺伝子群の発現を検討することで、未分化転化や高い悪性度のメカニズムが解明でき、新たな治療に繋がる可能性がある。

Outline of Final Research Achievements

In this study, we investigated the significance of dedifferentiation for the development of anaplastic thyroid cancer, which is highly malignant and clinically important. By examining the expression of pluripotent genes, we hypothesized that the mechanism of undifferentiated conversion and high malignancy could be elucidated, leading to new treatments. By analyzing the expression status of pluripotent genes in clinical samples (pathological tissues) of undifferentiated thyroid cancer, and the gene expression status of undifferentiated thyroid cancer with modifying the data of public microarrays, we showed that the highly malignant region was coincided with high expression of pluripotency-related genes. These results support the hypothesis of undifferentiated conversion associated with pluripotent genes expression. In the future, blocking pluripotency-related networks may lead to new treatments for anaplastic thyroid cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究では悪性度が高く臨床的な重要度も高い甲状腺未分化がんの発生メカニズムを臨床組織サンプルを用いて検討した。甲状腺未分化がんの病理組織において、ES/iPS細胞で高発現している未分化性を保つ遺伝子（多能性関連遺伝子）の発現状況を検討したところ、多能性関連遺伝子の強発現が未分化転化を促進していると考えられる結果であった。今後、多能性関連ネットワークを阻害する薬剤（たとえばiPS 細胞の形成を阻害すると報告されている薬剤など）が、甲状腺未分化がんの新たな治療に繋がる可能性がある。

Research Products

• [Journal Article] DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency (2021)
  • Author(s): Taguchi Jumpei、Shibata Hirofumi、Kabata Mio、Kato Masaki、Fukuda Kei、Tanaka Akito、Ohta Sho、Ukai Tomoyo、Mitsunaga Kanae、Yamada Yosuke、Nagaoka So I、Yamazawa Sho、Ohnishi Kotaro、Woltjen Knut、Ushiku Tetsuo、Ozawa Manabu、Saitou Mitinori、Shinkai Yoichi、Yamamoto Takuya、Yamada Yasuhiro
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5041-5041
  • DOI: 10.1038/s41467-021-25249-4
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial expression of Gata4 and Sox2 regulates specification of the squamous?columnar junction via MAPK/ERK signaling in mice (2021)
  • Author(s): Sankoda Nao、Tanabe Wataru、Tanaka Akito、Shibata Hirofumi、Woltjen Knut、Chiba Tsutomu、Haga Hironori、Sakai Yoshiharu、Mandai Masaki、Yamamoto Takuya、Yamada Yasuhiro、Uemoto Shinji、Kawaguchi Yoshiya
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1-15
  • DOI: 10.1038/s41467-021-20906-0
  • Peer Reviewed / Open Access
• [Journal Article] In vivo reprogramming drives Kras-induced cancer development (2018)
  • Author(s): Shibata Hirofumi、Komura Shingo、Yamada Yosuke、Sankoda Nao、Tanaka Akito、Ukai Tomoyo、Kabata Mio、Sakurai Satoko、Kuze Bunya、Woltjen Knut、Haga Hironori、Ito Yatsuji、Kawaguchi Yoshiya、Yamamoto Takuya、Yamada Yasuhiro
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2081-2081
  • DOI: 10.1038/s41467-018-04449-5
  • NAID: 120006473761
  • Peer Reviewed / Open Access
• [Journal Article] Srf destabilizes cellular identity by suppressing cell-type-specific gene expression programs (2018)
  • Author(s): Ikeda Takashi、Hikichi Takafusa、Miura Hisashi、Shibata Hirofumi、Mitsunaga Kanae、Yamada Yosuke、Woltjen Knut、Miyamoto Kei、Hiratani Ichiro、Yamada Yasuhiro、Hotta Akitsu、Yamamoto Takuya、Okita Keisuke、Masui Shinji
  • Journal Title: Nature Communications Volume: 9 Pages: 1387-1387
  • NAID: 120006517799
  • Peer Reviewed / Open Access
• [Presentation] 甲状腺未分化癌における多能性関連遺伝子群の発現 (2019)
  • Author(s): 柴田 博史, 大橋 敏充, 西堀 丈純, 久世 文也, 青木 光広
  • Organizer: 第43回 日本頭頸部癌学会
• [Presentation] 甲状腺未分化癌における多能性関連遺伝子群の発現 (2019)
  • Author(s): 柴田 博史, 大橋 敏充, 林 寿光, 西堀 丈純, 久世 文也, 青木 光広
  • Organizer: 日本頭頸部癌学会
• [Book] Medical Applications of iPS Cells (2019)
  • Author(s): Shibata H, Yamada Y
  • Total Pages: 15
  • Publisher: Springer 社
  • ISBN: 9789811336720
• [Book] Medical Applications of iPS Cells (2019)
  • Author(s): Hirofumi Shibata, Yasuhiro Yamada
  • Total Pages: 15
  • Publisher: Springer
  • ISBN: 9789811336713