Elucidating the mechanisms of pre-metastatic niche formation by pancreatic cancer exosomes

• Project/Area Number: 17K10702
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: MIYOSHI Kei 九州大学, 大学病院, 助教 (70755272)
• Co-Investigator(Kenkyū-buntansha): 江上 拓哉 九州大学, 医学研究院, 共同研究員 (40507787) ; 宮坂 義浩 九州大学, 医学研究院, 共同研究員 (40507795) ; 大内田 研宙 九州大学, 大学病院, 講師 (20452708)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵癌 / エクソソーム / 肝転移 / 微小環境 / 癌間質相互作用 / 膵星細胞 / PSC / オルガノイド

Outline of Final Research Achievements

The purpose of this study is to identify the exosomes that induce liver metastasis of pancreatic cancer, and to clarify the factors involved in liver metastasis of pancreatic cancer and the mechanism of microenvironment modification of the metastasis destination. Exosomes were extracted from pancreatic juice collected from pancreatic cancer patients, and candidates for miRNA specific to pancreatic cancer-derived exosomes were identified. In addition, we constructed a mouse model with liver metastasis and clarified that high CD110 expression in pancreatic cancer cells is associated with liver metastasis and poor prognosis. These data support that reprogramming the microenvironment in primary and metastatic niche might be a promising approach for new therapy of pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

膵癌は早期に転移を形成することで知られ、転移のメカニズム解明は治療法の確立にも必須である。本研究では膵癌由来エクソソームの同定、また肝転移形成のメカニズムに関して原発巣のみならず転移先の微小環境因子から明らかにすることで、癌微小環境制御という観点から既存の治療と異なるアプローチが期待できるものと考えられる。

Research Products

• [Journal Article] Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer-associated fibroblasts (2019)
  • Author(s): Takesue S、Ohuchida K、Shinkawa T、Otsubo Y、Matsumoto S、Sagara A、Yonenaga A、Ando Y、Kibe S、Nakayama H、Iwamoto C、Shindo K、Moriyama T、Nakata K、Miyasaka Y、Ohtsuka T、Toma H、Tominaga Y、Mizumoto K、Hashizume M、Nakamura M
  • Journal Title: International Journal of Oncology Volume: 56 Pages: 596-605
  • DOI: 10.3892/ijo.2019.4951
  • Peer Reviewed / Open Access
• [Journal Article] CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis. (2019)
  • Author(s): Yan Z, Ohuchida K, Zheng B, Okumura T, Takesue S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M
  • Journal Title: J Cancer Res Clin Oncol. Volume: 145 Issue: 5 Pages: 1147-1164
  • DOI: 10.1007/s00432-019-02860-z
  • Peer Reviewed / Open Access
• [Journal Article] Pancreatic juice exosomal microRNAs as biomarkers for detection of pancreatic ductal adenocarcinoma (2019)
  • Author(s): Nakamura S, Sadakari Y, Ohtsuka T, Okayama T, Nakashima Y, Gotoh Y, Saeki K, Mori Y, Nakata K, Miyasaka Y, Onishi H, Oda Y, Goggins M, Nakamura M.
  • Journal Title: Ann Surg Oncol Volume: 印刷中 Issue: 7 Pages: 2104-11
  • DOI: 10.1245/s10434-019-07269-z
  • Peer Reviewed
• [Presentation] A Novel Target That Required for Autophagy, Associated With Activation of Pancreatic Stellate Cells, Promotes Pancreatic Cancer Progression (2019)
  • Author(s): Guan W, Nakata K, Ohuchida K, Sagara A, Endo S, Ando Y, Yan Z, Matsumoto S, Shinkawa T, Ohtsubo Y, Iwamoto C, Moriyama T, Ikenaga N, Shindo K, Ohtsuka T, Mizumoto K, Nakamura M
  • Organizer: The 50th Annual Meeting of the American Pancreatic Association(APA)
• [Presentation] 好中球細胞外トラップ(NET)が膵癌肝転移巣おける癌関連線維芽細胞の誘導に与える影響の検討 (2019)
  • Author(s): 武居晋、大内田研宙、松本奏吉、新川智彦、大坪慶輝、相良亜希子、米永晃子、関維雨、馮海旻、安藤陽平、岐部晋、木庭遼、中山宏道、厳子龍、進藤幸治、仲田興平、森山大樹、宮坂義浩、永井俊太郎、大塚隆生、中村雅史
  • Organizer: 第119回日本外科学会定期学術集会