Analysis of transcriptome in the tumor microenvironment to explore the pathogenesis and new treatment strategies of human pancreatic cancer.

• Project/Area Number: 19K08362
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hamada Tsuyoshi 東京大学, 医学部附属病院, 助教 (90723461)
• Co-Investigator(Kenkyū-buntansha): 立石 敬介 東京大学, 医学部附属病院, 講師 (20396948) ; 中井 陽介 東京大学, 医学部附属病院, 准教授 (80466755)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 膵癌 / ヒト / 微小環境 / 分子病理疫学 / 予後解析 / サブタイプ / トランスクリプトーム

Outline of Research at the Start

様々な癌における腫瘍細胞の不均一性heterogeneityは薬剤耐性などにも関わることから重要な研究課題である。一方で腫瘍組織を構成する癌以外の間質細胞プロファイルについての多様性も明らかにされつつある。本研究ではヒト膵癌における腫瘍細胞および間質細胞の多様性を解析し、原発組織の病理学的特性および疫学的・臨床データと統合、相関を解析することで包括的なヒト膵癌の理解を目指す。

Outline of Final Research Achievements

The microenvironment of pancreatic cancer consists of tumor cells and a variety of cells in the surrounding stroma. In addition to this immunosuppressive tumor microenvironment, intratumor heterogeneity can lead to progression of tumor cells and treatment resistance. A better understanding of the dynamic network in the tumor microenvironment would help us to improve treatment strategies and prolong survival of patients with pancreatic cancer.
Utilizing a multi-institutional cohort of patients with pancreatic cancer, we have shown that KRAS variant allele frequency is inversely associated with recurrence-free and overall survival times. We now conduct gene expression analyses based on profiling of protein and RNA expressions. We will further integrate data on epidemiological factors (common medications, smoking, etc.) into our molecular database and aim to improve prognosis of pancreatic cancer patients through personalizing treatment strategies.

Academic Significance and Societal Importance of the Research Achievements

多施設での組織検体を用いて、膵癌発生に関連する主要な遺伝子変異であるKRAS変異を評価し、膵癌組織においてこの遺伝子変異をもつ細胞の割合が高いほど術後の再発率が高く、生存予後が不良であることを示した。この新たなバイオマーカー（予測因子）の発見により、より集学的な治療を要する膵癌患者の一群を同定し、今後の治療法開発や個別化治療への発展に寄与する結果を得た。現在、その他の因子（遺伝子の発現や、タンパク発現）の評価を進めており、さらに複合的なデータに基づいて膵癌患者の治療戦略をより良いものとすることを目指す。

Research Products

• [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] KRAS variant allele frequency, but not mutation positivity, associates with survival of patients with pancreatic cancer (2022)
  • Author(s): Suzuki T, Masugi Y, Inoue Y, Hamada T, Tanaka M, Takamatsu M, Arita J, Kato T, Kawaguchi Y, Kunita A, Nakai Y, Nakano Y, Ono Y, Sasahira N, Takeda T, Tateishi K, Uemura S, Koike K, Ushiku T, Takeuchi K, Sakamoto M, Hasegawa K, Kitago M, Takahashi Y, Fujishiro M.
  • Journal Title: Cancer Science Volume: - Issue: 9 Pages: 3097-3109
  • DOI: 10.1111/cas.15398
  • 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 Epidemiology, Biomarkers and Prevention Volume: 30 Issue: 5 Pages: 1020-1028
  • DOI: 10.1158/1055-9965.epi-20-1581
  • Peer Reviewed