Elucidation of the mechanism of pancreatic cancer metastasis using single cell analysis technology and innovative mouse models

• Project/Area Number: 18K19546
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Osaka University
• Principal Investigator: Takehara Tetsuo 大阪大学, 医学系研究科, 教授 (70335355)
• Co-Investigator(Kenkyū-buntansha): 小玉 尚宏 大阪大学, 医学系研究科, 助教 (10623275)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 膵癌 / 肝転移 / 免疫逃避 / HLA / シングルセル解析 / マウスモデル / 転移 / エレクトロポレーション / レンチウイルス / 遺伝子導入 / 単一細胞解析 / CIRPSR/Cas / マウス

Outline of Final Research Achievements

The purpose of this study was to elucidate the molecular basis of pancreatic cancer metastasis by analyzing clinical samples of human pancreatic cancer using comprehensive gene expression analysis technology in single cells and basic research using an innovative mouse model of pancreatic cancer based on genome editing technology. We have succeeded in establishing a mouse model that develops pancreatic cancer by inducing activation and inactivation of oncogenes such as Kras and Tp53 in a pancreas-specific and time-dependent manner through the fusion of gene-edited mice and electroporation technology. We also conducted single-cell gene expression analysis using primary tissues and liver metastasis tissues of pancreatic cancer patients, and found that down-regulation of HLA molecules in cancer cells at metastasis sites may contribute to escape from immune surveillance mechanisms and promote metastasis.

Academic Significance and Societal Importance of the Research Achievements

膵臓がんは非常に難治であり、原発巣が非常に小さな腫瘍の段階から高率に肝臓などの多臓器へ転移し、進展する。転移を伴う膵癌の予後は極めて不良であり、その予後改善には転移の分子基盤や転移抑制を目指した治療開発が極めて重要である。本研究により膵癌細胞が免疫機構からの逃避を促進することで転移が促されるといいう新たな分子基盤を見出しており、転移抑制を目指した治療開発において極めて重要な結果であると考えられる。また、今後見出した分子の治療標的としての有用性を生体モデルで検討するための基盤となるマウスモデルの樹立が出来た点も今後の研究発展や臨床への展開に重要な意義があると考えられる。

Research Products

• [Journal Article] Risk Factors for Pancreatic Cancer and the Necessity of Long-Term Surveillance in Patients With Pancreatic Cystic Lesions (2020)
  • Author(s): Yoshioka Teppei、Shigekawa Minoru、Ikezawa Kenji、Tamura Takeshi、Sato Katsuhiko、Urabe Makiko、Sueyoshi Hironari、Yamai Takuo、Suda Takahiro、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Pancreas Volume: 49 Issue: 4 Pages: 552-560
  • DOI: 10.1097/mpa.0000000000001521
  • Peer Reviewed
• [Journal Article] Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels (2020)
  • Author(s): Sato Katsuhiko、Hikita Hayato、Myojin Yuta、Fukumoto Kenji、Murai Kazuhiro、Sakane Sadatsugu、Tamura Takeshi、Yamai Takuo、Nozaki Yasutoshi、Yoshioka Teppei、Kodama Takahiro、Shigekawa Minoru、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: PLOS ONE Volume: 15 Issue: 7 Pages: e0235573-e0235573
  • DOI: 10.1371/journal.pone.0235573
  • Peer Reviewed
• [Journal Article] Endoscopic biliary stenting as the risk factor for cholangitis after endoscopic ultrasound in patients with biliary strictures (2020)
  • Author(s): Ikezawa Kenji、Shigekawa Minoru、Yamai Takuo、Suda Takahiro、Kegasawa Tadashi、Yoshioka Teppei、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: in press Issue: 5 Pages: 1263-1266
  • DOI: 10.1111/jgh.15264
  • Peer Reviewed
• [Presentation] 炎症制御分子Regnase-1を介した膵癌発症機構の解明 (2020)
  • Author(s): 岡部純弥、小玉尚宏、竹原徹郎
  • Organizer: JDDW2020
• [Presentation] 膵多血性腫瘍に対するEUS-FNAの工夫 (2020)
  • Author(s): 清田良介、重川 稔、吉岡鉄平、竹原徹郎
  • Organizer: 第105回日本内視鏡学会近畿支部例会
• [Presentation] 長期経過観察例からみる自己免疫性膵炎の課題 (2020)
  • Author(s): 重川 稔、吉岡鉄平、竹原徹郎
  • Organizer: 第51回日本膵臓学会
• [Presentation] 慢性膵炎におけるHippo/PI3K経路の調節不全と治療標的としての可能性 (2020)
  • Author(s): 田村猛、小玉尚宏、吉岡鉄平、重川稔、疋田隼人、阪森亮太郎、秋田裕史、江口英利、巽智秀、竹原徹郎
  • Organizer: 第51回日本膵臓学会大会
• [Presentation] がん特異的アミノ酸トランスポータを標的とした膵癌治療の可能性 (2019)
  • Author(s): 野崎 泰俊、疋田 隼人、竹原 徹郎
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] THE RELATIONSHIP BETWEEN OBSERVATION INTERVAL AND PROGNOSIS IN PANCREATIC CANCER ASSOCIATED WITH PANCREATIC CYSTIC LESIONS (2019)
  • Author(s): Teppei Yoshioka, Minoru Shigekawa, Yu Sato, Junya Okabe, Takeshi Tamura, Katsuhiko Sato, Makiko Urabe, Takuo Yamai, Takahiro Suda, Ryoko Yamada, Takahiro Kodama, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi and Tetsuo Takehara
  • Organizer: Digestive Disease Week (DDW2019)
  • Int'l Joint Research