Elucidation of leading PSC induced basement membrane destruction mechanism and development of the regulating method by using pancreatic organoids

• Project/Area Number: 17H04284
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: OHUCHIDA Kenoki 九州大学, 大学病院, 講師 (20452708)
• Co-Investigator(Kenkyū-buntansha): 岩本 千佳 九州大学, 大学病院, 特任助教 (10752842) ; 大塚 隆生 九州大学, 医学研究院, 准教授 (20372766) ; 村田 正治 九州大学, 先端医療イノベーションセンター, 特任教授 (30304744) ; 藤田 逸人 九州大学, 医学研究院, 助教 (40611281) ; 池永 直樹 九州大学, 大学病院, 助教 (90759755) ; 宮坂 義浩 九州大学, 大学病院, 助教 (40507795)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 膵癌 / 膵星細胞 / リーディングセル / 基底膜破壊 / MMP2 / MT1-MMP / 膵臓癌 / 基底膜 / 癌関連マクロファージ / オルガノイド / PSC / 膵オルガノイド

Outline of Final Research Achievements

In this study, we investigated how pancreatic stellate cells (PSCs) disrupt the basement membrane of pancreatic cancer tissue and support the invasion of pancreatic cancer cells by using pancreatic cancer organoids, and aimed to develop a regulating method therefor. Pancreatic cancer organoids formed a basement membrane similar to the pancreatic cancer tissue, and a three-dimensional co-culture model with PSCs revealed that PSCs promoted pancreatic cancer cell invasion through basement membrane destruction in real time observation. In addition, it was clarified through in vitro / in vivo assays by RNA interference that the basement membrane destruction mediated by MMP2 and MT1-MMP of PSCs supported pancreatic cancer cell invasion. In the future, we will identify specific pancreatic stellate cells that function as leading cells and develop a novel method for regulating pancreatic cancer invasion by controlling them.

Academic Significance and Societal Importance of the Research Achievements

膵癌の予後を規定する癌浸潤メカニズムを解明するために、膵星細胞のleading cellとしての機能に着目して研究を行い、膵星細胞がMMP2およびMT1-MMPによる基底膜破壊を介して膵癌細胞浸潤を支持していることを解明した。膵星細胞のleading cellとしての機能を解明した研究はこれまでになく、これらを制御することで膵癌細胞浸潤を抑制する新規の制御法の開発が可能となった。その制御法を確立し臨床応用することによって今後の膵癌患者の予後改善に寄与し得ると考えられる。

Research Products

• [Journal Article] An In Vitro Three-Dimensional Organotypic Model to Analyze Peripancreatic Fat Invasion in Pancreatic Cancer: A Culture System Based on Collagen Gel Embedding. (2019)
  • Author(s): Okumura T, Ohuchida K, Nakamura M.
  • Journal Title: Methods Mol Biol. Volume: 1882 Pages: 135-141
  • DOI: 10.1007/978-1-4939-8879-2_11
  • ISBN: 9781493988785, 9781493988792
  • Peer Reviewed
• [Journal Article] Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma (2018)
  • Author(s): Koikawa K、Ohuchida K、Ando Y、Kibe S、Nakayama H、Takesue S、Endo S、Abe T、Okumura T、Iwamoto C、Moriyama T、Nakata K、Miyasaka Y、Ohtsuka T、Nagai E、Mizumoto K、Hashizume M、Nakamura M
  • Journal Title: Cancer Letters Volume: 425 Pages: 65-77
  • DOI: 10.1016/j.canlet.2018.03.031
  • Peer Reviewed / Open Access
• [Presentation] BM-Derived Cells Destruct Basement Membrane and Induce Local Invasion of Pancreatic Cancer (2019)
  • Author(s): Iwamoto C, Ohuchida K, Ando Y, Shinkawa T, Ohtsubo Y, Shindo K, Moriyama T, Nakata K, Miyawaki K, Ohtsuka T, Akashi K, Eto M, Nakamura M
  • Organizer: The 50th Annual Meeting of the American Pancreatic Association(APA)
  • Int'l Joint Research
• [Presentation] 膵癌微小環境を構築する骨髄由来細胞が膵癌浸潤を先導する (2019)
  • Author(s): 岩本千佳、大内田研宙、安藤陽平、新川智彦、大坪慶志輝、進藤幸治、森山大樹、仲田興平、宮脇恒太、赤司浩一、江藤正俊、中村雅史
  • Organizer: 第78回日本癌学会学術集会
• [Presentation] 膵臓に誘導され膵癌微小環境を構成する骨髄由来細胞が膵癌浸潤を制御する (2019)
  • Author(s): 岩本千佳、大内田研宙、武居晋、進藤幸治、宮脇恒太、赤司浩一、橋爪誠、江藤正俊、中村雅史
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] 膵癌局所浸潤部における癌関連腺房導管異型性は癌局所浸潤に寄与する (2019)
  • Author(s): 岐部晋、大内田研宙、新川智彦、大坪慶志輝、松本奏吉、相良亜希子、米永晃子、馮海旻、関維雨、安藤陽平、武居晋、中山宏道、厳子龍、進藤幸治、森山大樹、仲田 興平、永井俊太郎、宮坂義浩、大塚隆生、水元一博、中村雅史
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] Endo180 Expression and Histologic Categorization in Cancer Stroma is an Independent Prognostic Index in Pancreatic Cancer. (2018)
  • Author(s): Koikawa K, Ohuchida K, Yonenaga A, Sagara A, Ando Y, Kibe S, Takesue S,Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Nakamura M
  • Organizer: 49th Annual Meeting of the APA
  • Int'l Joint Research
• [Presentation] Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma (2018)
  • Author(s): Koikawa K, Ohuchida K, Ando Y, Kibe S, Nakayama H, Takesue S, Endo S, Abe T, Okumura T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M
  • Organizer: Pancreas 2018
  • Int'l Joint Research
• [Presentation] 膵オルガノイドを用いた浸潤性膵管癌の新たな局所微小浸潤機序の解明 (2018)
  • Author(s): 米永晃子、肥川和寛、大内田研宙、進藤幸治、仲田興平、森山大樹、宮坂義浩、大塚隆生、水元一博、中村雅史
  • Organizer: 第49回日本膵臓学会大会
• [Presentation] Pancreatic organoids elucidate the new mechanisms of pancreatic cancer local invasion (2017)
  • Author(s): Koikawa K, Ohuchida K, Ando Y, Kibe S, Nakayama H, Takesue S, Yan Z, Abe T, Okumura T, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Okabe Y, Ohtsuka T, Mizumoto K, Nakamura M
  • Organizer: The 48th Annual Meeting of The American Pancreatic Association
  • Int'l Joint Research