Exploration of biomarkers and therapeutic targets for pancreatic ductal papillary mucinous tumor-associated pancreatic cancer from the GNAS pathway

• Project/Area Number: 20K17009
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Asahikawa Medical College
• Principal Investigator: Kawabata Hidemasa 旭川医科大学, 医学部, 助教 (50548691)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: IPMN / 膵臓癌 / GNAS / KRAS / 膵癌 / Notchシグナル / 膵管内乳頭粘液性腫瘍 / GNAS変異

Outline of Research at the Start

GNAS変異は膵癌前駆病変のひとつである膵管内乳頭粘液性腫瘍（IPMN）に特徴的なドライバー遺伝子である。同変異はマウスモデルにおいてKRASシグナルと協調しIPMNの発生を促すが、ヒトにおいて浸潤・転移などの悪性度に関わる分子経路をどのように制御するか十分に理解されていない。本研究の目的は、患者由来の膵初代培養系を用い、GNAS変異によって誘導される分子経路を特定することである。まず、同変異を有する初代細胞を用いて、ゲノム編集の応用によりGNAS変異が増殖や浸潤などの悪性形質に関わる分子経路に及ぼす影響を調べる。次に、代表的なKRASシグナルの下流経路に及ぼす影響を生化学的に検証する。

Outline of Final Research Achievements

Intraductal papillary mucinous tumor (IPMN) is a precancerous lesion of pancreatic cancer characterized by a cyst-like structure due to papillary growth and abundant mucus production, but its morphological characteristics and mechanisms involved in its progression to invasive cancer are unknown. In this analysis, GNAS, an important oncogene for IPMN, acts as a brake on the KRAS pathway through the suppression of Notch, and is considered to have a functional aspect of tumor suppression even though it is an oncogene. It was considered important in the development of drug therapies for pancreatic tumors that target the GNAS pathway.

Academic Significance and Societal Importance of the Research Achievements

膵癌の前がん病変であるIPMNにおける癌遺伝子KRASとGNASの解析を行うことで、今までにない新たなGNAS経路を標的とする膵癌薬物治療の開発につながる可能性がある。今後も解析を進めていきたい。

Research Products

• [Journal Article] Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway (2022)
  • Author(s): Kawabata Hidemasa、Ono Yusuke、Tamamura Nobue、Oyama Kyohei、Ueda Jun、Sato Hiroki、Takahashi Kenji、Taniue Kenzui、Okada Tetsuhiro、Fujibayashi Syugo、Hayashi Akihiro、ほか
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 3 Pages: 208-220
  • DOI: 10.1007/s00535-021-01846-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] IPMN関連膵癌におけるGNAS遺伝子の病態解明からみた治療戦略 (2023)
  • Author(s): 河端秀賢
  • Organizer: 第54回日本膵臓学会大会
• [Presentation] IPMN関連膵癌における変異型GNASによる腫瘍悪性度の制御 (2023)
  • Author(s): 河端秀賢
  • Organizer: 第109回日本消化器病学会総会
• [Presentation] Tumor-suppressive effect of mutant GNAS through the restriction of tumor aggressiveness in established pancreatic cancer. (2022)
  • Author(s): Hidemasa Kawabata
  • Organizer: DDW2022/AGA2022
  • Int'l Joint Research
• [Presentation] Mutant GNAS limits tumor aggressiveness in established pancreatic cancer via antagonizing the KRAS-pathway. (2022)
  • Author(s): Hidemasa Kawabata
  • Organizer: 第26回国際膵臓学会 Oral 27 IPMN(Basic Research)
  • Int'l Joint Research
• [Presentation] IPMN関連膵癌におけるPKA-GNAS経路による悪性度制御. (2022)
  • Author(s): 河端秀賢
  • Organizer: 第7回 Gastro-PLUS 口頭発表
• [Presentation] TUMOR-SUPPRESSIVE EFFECT OF MUTANT GNAS THROUGH THE RESTRICTION OF TUMOR AGGRESSIVENESS IN ESTABLISHED PANCREATIC CANCER (2022)
  • Author(s): Hidemasa Kawabata
  • Organizer: DDW2022, Digestive disease week, Sandiego
  • Int'l Joint Research
• [Book] 膵癌・胆道癌 2023 (上) 膵癌編 ―基礎・臨床の最新研究動向― II.各 論 81巻 増刊号2 (2023)
  • Author(s): 河端秀賢、高橋賢治、水上裕輔
  • Publisher: 日本臨牀
• [Book] 膵癌・胆道癌2023 上 膵癌編 (2023)
  • Author(s): 河端秀賢
  • Total Pages: 13
  • Publisher: 日本臨床 増刊号