Comprehensive analyses about factors involved in the progression from IPMN to Pancreatic cancer

• Project/Area Number: 20K16154
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Saito Kei 東京大学, 医学部附属病院, 届出研究員 (20815617)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 膵がん / 膵癌

Outline of Research at the Start

臨床的に膵癌の高危険群のひとつと考えられている膵管内乳頭粘液性腫瘍（Intraductal papillary mucinous neoplasm; IPMN）のうち、浸潤癌に進展する規定因子の同定を、GNAS変異導入ヒト膵管上皮細胞と膵癌細胞株を用いて、遺伝子編集によるノックアウトライブラリーと次世代シークエンスによって網羅的に試みる。本研究で、GNAS変異を持つIPMN患者の中での膵癌進行の病態生理を明らかにすることにより、IPMNの中でもさらに膵癌の高危険群の新たな絞り込み法を確立し、効率的な膵癌スクリーニングにつなげる。

Outline of Final Research Achievements

IPMN, a cystic disease of the pancreas, is a precancerous pathology of pancreatic cancer. We investigated to identify essential genes in the process from IPMN-like pathology with GNAS mutation to invasive cancer.
As a result, the GNAS mutation caused the GNAS protein to bind to Ran, a chaperone protein that connects the cell nucleus and cytoplasm, resulting in changes in intracellular signaling other than the MAPK pathway, resulting in an increase in chemokine expression and the cell undergoing apoptosis. It was assumed that the cells would fall and increase cell turnover.
Since the increase in cell turnover directly leads to the accumulation of gene mutations, this was considered to be one of the mechanisms of pancreatic carcinogenesis from IPMN.

Academic Significance and Societal Importance of the Research Achievements

年率1-2%と言われるGNAS変異を持つIPMN様病態から浸潤癌に至る人がなぜ存在するのか、GNAS変異から浸潤癌に至るまでの過程における必須の遺伝子を同定することは重要である。今回IPMNからの膵発癌機構のひとつを同定したが、今後これらの機構を追求することで、IPMNからの膵発癌を抑制する手法を開発することに繋がることが期待される。

Research Products

• [Journal Article] Early skeletal muscle mass decline is a prognostic factor in patients receiving gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer: a retrospective observational study (2023)
  • Author(s): Suzuki Yukari、Saito Kei、Nakai Yousuke、Oyama Hiroki、Kanai Sachiko、Suzuki Tatsunori、Sato Tatsuya、Hakuta Ryunosuke、Ishigaki Kazunaga、Saito Tomotaka、Hamada Tsuyoshi、Takahara Naminatsu、Tateishi Ryosuke、Fujishiro Mitsuhiro
  • Journal Title: Supportive Care in Cancer Volume: 31 Issue: 3 Pages: 197-197
  • DOI: 10.1007/s00520-023-07659-w
  • Peer Reviewed / Open Access
• [Journal Article] MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages (2022)
  • Author(s): Kato H, Tateishi K, Fujiwara H, Nakatsuka T, Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito K, Saito T, Takahara N, Kishikawa T, Hamada T, Takahashi R, Miyabayashi K, et al.
  • Journal Title: Gastroenterology Volume: 162 Issue: 4 Pages: 1272-1287
  • DOI: 10.1053/j.gastro.2021.12.254
  • Peer Reviewed / Open Access
• [Journal Article] ABO Blood Group and Risk of Pancreatic Carcinogenesis in Intraductal Papillary Mucinous Neoplasms (2021)
  • Author(s): Hamada T, Oyama H, Nakai Y, Tada M, Koh H, Tateishi K, Arita J, Hakuta R, Ijichi H, Ishigaki K, Kawaguchi Y, Kogure H, Mizuno S, Morikawa T, Saito K, Saito T, Sato T, Takagi K, Takahara N, Takahashi R, Tanaka A, Tanaka M, Ushiku T, Hasegawa K, Koike K.
  • Journal Title: Cancer Epidemiol Biomarkers Prev . Volume: 30 Pages: 1020-1028
  • Peer Reviewed
• [Journal Article] A retrospective comparative study of S-IROX and modified FOLFIRINOX for patients with advanced pancreatic cancer refractory to gemcitabine plus nab-paclitaxel (2020)
  • Author(s): Saito Kei、Nakai Yousuke、Takahara Naminatsu、Ishigaki Kazunaga、Suzuki Yukari、Inokuma Akiyuki、Noguchi Kensaku、Kanai Sachiko、Sato Tatsuya、Hakuta Ryunosuke、Saito Tomotaka、Hamada Tsuyoshi、Mizuno Suguru、Kogure Hirofumi、Ijichi Hideaki、Tateishi Keisuke、Koike Kazuhiko
  • Journal Title: Investigational New Drugs Volume: 39 Issue: 2 Pages: 605-613
  • DOI: 10.1007/s10637-020-01022-0
  • Peer Reviewed / Open Access