Control of microenvironment involved in pancreatic cancer progression and defense by phenotype switching

• Project/Area Number: 17K19602
• 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: OHUCHIDA Kenoki 九州大学, 大学病院, 講師 (20452708)
• Co-Investigator(Kenkyū-buntansha): 寅田 信博 九州大学, 大学病院, 臨床検査技師 (00398075) ; 前山 良 九州大学, 医学研究院, 共同研究員 (10611668) ; 江上 拓哉 九州大学, 医学研究院, 共同研究員 (40507787) ; 藤田 逸人 九州大学, 医学研究院, 助教 (40611281)
• 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 / 癌微小環境 / phenotype switching / 膵癌微小環境 / オルガノイド

Outline of Final Research Achievements

Pancreatic stellate cells (PSCs) have a pivotal role in cancer-associated fibroblasts (CAFs) and have a functional heterogeneity. The aim of this study is to clarify the functional heterogeneity of PSCs and to establish a new strategy of PSCs targeting the phenotype switching. We have obtained new findings on the identification of PSCs derived from adipose stem cells and bone marrow stem cells and their involvement in cancer progression. We also constructed the pseudo model of microenvironment by 3D co-culture of pancreatic cancer organoids and PSCs and found new mechanisms regarding the local progression of cancer cells and PSCs. Based on these results we found the possibility targeting the phenotype switching of PSCs.

Academic Significance and Societal Importance of the Research Achievements

膵癌は悪性度の高い癌であり、その要因の一つにdesmoplasiaと呼ばれる過剰な間質増生がある。そのため間質を標的とした治療法の検討が示されてきたが、これまでの臨床研究では間質減量治療の有効性は示されていない。本研究では、膵癌における間質細胞の多様性や産生される基質の特性を明らかにし、癌進展に促進的もしくは防御的に機能する細胞集団を同定し、その機序を解明するため、膵癌微小環境を構成する細胞を用いた擬似的な解析モデルを多数作製し、各種由来間質細胞の多様な役割について明らかにした。これらの結果は癌微小環境の更なる病態理解とともに、微小環境を標的とした新規治療法の開発につながるものと期待される。

Research Products

• [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] 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] Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix (2018)
  • Author(s): Okumura T, Ohuchida K, Kibe S, Iwamoto C, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Sada M, Horioka K, Mochidome N, Arita M, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M
  • Journal Title: Int J Cancer Volume: 144 Issue: 6 Pages: 1401-1413
  • DOI: 10.1002/ijc.31775
  • Peer Reviewed / Open Access
• [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] 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] Fat tissue and pancreatic parenchyma play different roles in pancreatic cancer invasion (2018)
  • Author(s): Ohuchida K, Kibe S, Okumura T, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Nakamura M
  • Organizer: Pancreas 2018
  • Int'l Joint Research