Elucidation of mechanism of PSC leading to pancreatic cancer cluster invasion and pancreatic cancer control by microenvironmental substrate remodeling

• Project/Area Number: 17K19607
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kyushu University
• Principal Investigator: IKENAGA Naoki 九州大学, 医学研究院, 共同研究員 (90759755)
• Co-Investigator(Kenkyū-buntansha): 井上 重隆 九州大学, 医学研究院, 共同研究員 (00529802) ; 前山 良 九州大学, 医学研究院, 共同研究員 (10611668) ; 藤田 逸人 九州大学, 医学研究院, 助教 (40611281) ; 森山 大樹 九州大学, 大学病院, 准教授 (70586859) ; 大内田 研宙 九州大学, 大学病院, 講師 (20452708)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 膵癌 / 膵星細胞 / leading cells / クラスター浸潤 / 微小環境基質改変 / 基質リモデリング

Outline of Final Research Achievements

Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. Invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. In addition, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs. Next, we established human PDAC organoids from resected PDAC specimens. When the organoids were co-cultured with PSCs, organoids lost their BM and ductal structures by PSCs direct contact and invaded collagen matrix more frequently. Matrix metalloproteinase 2 or membrane type-1 MMP knockdown in PSCs significantly attenuated BM destruction by PSC.

Academic Significance and Societal Importance of the Research Achievements

癌細胞は様々な形態で浸潤・転移を行う。本研究では、クラスター浸潤を導くPSCが形成する浸潤微小環境を改変することで癌の進展制御を目指した。その結果、Endo180ノックダウンPSCは、インビボで共移植された膵臓癌モデルにおける腫瘍増殖および局所浸潤を減少させる、またヒト膵癌由来オルガノイドを樹立し、PSCの直接接触でオルガノイドの基底膜が破壊されることを見出した。この研究は、今までの膵癌の浸潤・転移に関する研究とは全く異なるアプローチによる研究であり、予後改善が進まない膵癌治療を進展させる一助となりうる可能性があり、学術的意義、社会的意義は大きいと思われる。

Research Products

• [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
• [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