Elucidation of the difference in extracellular matrix remodeling ability of pancreatic stellate cells depending on pancreatic cancer phenotype via organoid models

• Project/Area Number: 16H06258
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: IKENAGA Naoki 九州大学, 大学病院, 助教 (90759755)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥23,920,000 (Direct Cost: ¥18,400,000、Indirect Cost: ¥5,520,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 膵癌 / オルガノイド / 膵星細胞 / 癌周囲微小環境 / 基質リモデリング / 癌微小環境 / 分化型 / 遺伝子改変膵オルガノイド / 膵癌phenotype / PSC / phenotype

Outline of Final Research Achievements

This study was performed to classify the phenotype of pancreatic cancer organoids derived from human pancreatic tissue and to clarify the difference in the extracellular matrix (ECM) remodeling ability of activated pancreatic stellate cells (PSCs) depending on the phenotypes. The organoids maintained the morphology of the pancreatic tissues, and phenotype classification was possible based on the niche factors dependency and the tumor differentiation. We established a three-dimensional co-culture model using the organoids and PSCs, and observed how the pancreatic cancer cells invade the ECM. These revealed that the basement membrane destruction by PSCs via MMP2 and MT1-MMP. In the future, we challenge to elucidate the differences in ECM remodeling by PSCs depending on each pancreatic cancer phenotype and to develop a personalized treatment that controls cancer cell invasion.

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上で、従来の細胞株のような単一的なphenotypeではなく、患者個々の膵癌組織から樹立した膵癌オルガノイドを用いることで様々な膵癌phenotypeに応じた浸潤形態を観察可能となった。本研究では、この膵癌オルガノイドと膵星細胞の三次元共培養モデルを作製することで、より生体内を反映した環境での浸潤形態を観察可能となり、膵星細胞のMMP2及びMT1-MMPを介した膵癌基底膜破壊が膵癌細胞浸潤に関わっていることを解明した。今後は、樹立した様々な膵癌phenotypeに応じた浸潤過程の差違を明らかにすることで、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
• [Journal Article] Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180 (2018)
  • Author(s): Koikawa K, Ohuchida K, Takesue S, Ando Y, Kibe S, Nakayama H, Endo S, Abe T, Okumura T, Horioka K, Sada M, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Ohuchida R, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M.
  • Journal Title: Cancer Letters Volume: 412 Pages: 143-154
  • DOI: 10.1016/j.canlet.2017.10.010
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy is required for activation of pancreatic sstellate cells, associated with pancreatic cancer progression and promotes growth of pancreatic tumors in mice. (2017)
  • Author(s): Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, Zheng B, Mizuuchi Y, Iwamoto C, Murata M, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M.
  • Journal Title: Gastroenterology Volume: 印刷中 Issue: 6 Pages: 1492-1506
  • DOI: 10.1053/j.gastro.2017.01.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 膵癌微小環境の制御に着目した既存薬剤を用いた膵癌治療の新たな展開 (2019)
  • Author(s): 相良亜希子、仲田興平、山下智大、松本奏吉、大坪慶志輝、新川智彦、安藤陽平、大内田研宙、大塚隆生、中村雅史
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] N-Acetyl-Cysteineによる活性化膵星細胞の不活化の検討 (2019)
  • Author(s): 馮海旻、森山大樹、大内田研宙、厳子龍、武居晋、岐部晋、永井俊太郎、進藤幸治、仲田興平、大塚隆生、中村雅史
  • Organizer: 第119回日本外科学会定期学術集会
• [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] 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] 膵オルガノイドによる新たな膵癌局所微小浸潤機序の解明‐膵星細胞が誘導する基底膜破壊と間質浸潤‐ (2017)
  • Author(s): 肥川和寛、大内田研宙、岐部晋、安藤陽平、武居晋、中山宏道、阿部俊也、遠藤翔、奥村隆志、森山大樹、仲田興平、宮坂義浩、真鍋達也、大塚隆生、永井英司、水元一博、中村雅史
  • Organizer: 第117回日本外科学会定期学術集会
• [Presentation] 膵癌局所浸潤を先導するleading cell －膵星細胞がつくる膵癌局所微少環境の機序解明－ (2017)
  • Author(s): 肥川和寛、大内田研宙、安藤陽平、岐部晋、中山宏道、武居晋、森山大樹、仲田興平、宮坂義浩、真鍋達也、大塚隆生、永井英司、水元一博、中村雅史
  • Organizer: 第38回癌免疫外科研究会
• [Presentation] 膵オルガノイドを用いたリアルタイムイメージングによる新たな膵癌局所微小浸潤機序の解明 (2017)
  • Author(s): 肥川和寛、大内田研宙、森山大樹、仲田興平、宮坂義浩、真鍋達也、大塚隆生、永井英司、水元一博、中村雅史
  • Organizer: 第72回日本消化器外科学会総会
• [Presentation] Endo180 regulate phosphorylation of myosin light chain 2 activity and increase the ability of extracellular matrix remodeling in leading pancreatic stellate cells. (2016)
  • Author(s): Koikawa K, Ohuchida K, Kibe S, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Okumura T, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Nakamura M.
  • Organizer: The 47th Annual meeting of American Pancreatic Association
  • Place of Presentation: Boston(USA)
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] Establishment of Pancreatic Organoid from human and murine pancreas tissue. (2016)
  • Author(s): Koikawa K, Ohuchida K, et al
  • Organizer: The 20th meeting of the International conference of Pancreatology
  • Place of Presentation: Sendai(JAPAN)
  • Year and Date: 2016-08-06
  • Int'l Joint Research
• [Presentation] 膵癌浸潤を先導するleading cell‐膵星細胞の基質リモデリング機能と浸潤機序の解明‐ (2016)
  • Author(s): 肥川和寛
  • Organizer: 第71回日本消化器外科学会総会
  • Place of Presentation: アスティ徳島(徳島市）
  • Year and Date: 2016-07-15
• [Presentation] 膵星細胞は基質リモデリングにより、leading cell として膵癌浸潤を先導する (2016)
  • Author(s): 肥川和寛、大内田研宙、佐田政史、阿部俊也、遠藤翔、奥村隆志、堀岡宏平、森山大樹、宮坂義浩、真鍋達也、大塚隆生、大内田理一、植木隆、永井英司、水元一博、中村雅史
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪(大阪市）
  • Year and Date: 2016-04-14
• [Book] 【膵炎・膵がん】膵がん浸潤・転移における微小環境の病態 (2016)
  • Author(s): 大内田研宙、中村雅史
  • Total Pages: 250
  • Publisher: 最新医学社