Novel mechanism of acinar atrophy by pancreatic cancer microenvironment and its role in local invasion

• Project/Area Number: 18K07943
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kyushu University
• Principal Investigator: SHIMAMOTO Masaya 九州大学, 大学病院, 助教 (00457433)
• Co-Investigator(Kenkyū-buntansha): 岩本 千佳 九州大学, 大学病院, 特任助教 (10752842) ; 鬼丸 学 九州大学, 医学研究院, 共同研究員 (80529876) ; 水元 一博 九州大学, 大学病院, 准教授 (90253418) ; 大内田 研宙 九州大学, 大学病院, 講師 (20452708)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵癌 / 局所浸潤 / Acinar atrophy / 癌微小環境 / ADM / 腺房萎縮 / 微小環境 / 膵腺房細胞 / 膵星細胞 / 膵癌周囲微小環境

Outline of Final Research Achievements

In this study, we focused on the heterogeneity of the pancreatic cancer microenvironment and aimed to identify the cells responsible for inducing Acinar atrophy and to elucidate the mechanism in order to develop a new treatment for local invasion of pancreatic cancer. In the invasive front of human pancreatic cancer tissues, Acinar-to-ductal metaplasia (ADM)-like changes expressed TGFα were observed, and the expression of TGFα was associated with poor prognosis. Gene expression analysis also revealed phenotypic differences among cancer-associated ADM, sporadic ADM, and chronic pancreatitis ADM. These results suggest that the mechanism causing ADM varies depending on the tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to the invasion of pancreatic cancer cells into the parenchyma.

Academic Significance and Societal Importance of the Research Achievements

膵癌進展を抑制するには、癌間質を含めた膵癌微小環境におけるheterogeneityを理解する必要があり、本研究によって癌関連ADMとAcinar atrophyが膵癌細胞の膵臓実質浸潤に寄与していることが示唆された。これまでに膵癌周囲微小環境としての膵腺房細胞の萎縮を誘導する責任細胞や因子に着目した報告はなく、これらの結果は膵癌局所浸潤におけるAcinar atrophyの機序の解明につながるものであり、それらの制御法の開発が新たな膵癌局所浸潤の治療法の開発に結び付くものと期待される。

Research Products

• [Journal Article] Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5 (2020)
  • Author(s): Yohei Ando, Kenoki Ohuchida , Yoshiki Otsubo, Shin Kibe, Shin Takesue, Toshiya Abe, Chika Iwamoto, Koji Shindo, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Takao Ohtsuka, Yoshinao Oda, Masafumi Nakamura
  • Journal Title: PLOS ONE Volume: 15 Issue: 1 Pages: e0228015-e0228015
  • DOI: 10.1371/journal.pone.0228015
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion. (2019)
  • Author(s): Kibe S, Ohuchida K, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Okumura T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Shimamoto M, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M.
  • Journal Title: Cancer Lett Volume: 444 Pages: 70-81
  • DOI: 10.1016/j.canlet.2018.12.005
  • 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] 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
• [Presentation] Human macrophages-derived CAF-like cells lead the invasion of pancreatic cancer (2020)
  • Author(s): Iwamoto C, Ohuchida K, Shinkawa T, Otsubo Y, Shindo K, Moriyama T, Nakata K, Ohtsuka T, Nakamura M
  • Organizer: 14th World Congress of International Hepeto-Pancreato-Biliary Association
  • Int'l Joint Research
• [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] Necroptosis in Pancreatic Cancer Promotes Cancer Cell Migration and Invasion by Release of CXCL5 (2019)
  • Author(s): Ando K, Ohuchida K, Otsubo Y, Sagara A, Kibe S, Takesue S, Nakayama M, Shindo K, Moriyama T, Nakata K, Ohtsuka T, Mizumoto K, 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] 膵癌細胞への異なった細胞死誘導による遊走・浸潤能への影響の比較 (2019)
  • Author(s): 安藤陽平、大内田研宙、岐部晋、武居晋、中山宏道、森山大樹、仲田興平、宮坂義浩、大塚隆生、中村雅史
  • Organizer: 第74回日本消化器外科学会総会
• [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] ADM are Classified Three Distinct Phenotypical Profiles Depending on its Different Microenvironment (2018)
  • Author(s): S. Kibe, K. Ohuchida, Y. Ando, S. Takesue, M. Nakayama, T. Abe, S. Endo, K. Koikawa, T. Okumura, C. Iwamoto, K. Shindo, T. Moriyama, K. Nakata, S. Nagai, Y. Miyasaka, M. Shimamoto, T. Ohtsuka, K. Mizumoto, M. Nakamura.
  • Organizer: American Pancreatic Association Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] CD110の阻害は、マウスの膵癌肝転移を抑制する (2018)
  • Author(s): 厳子龍、大内田研宙、森山大樹、仲田興平、宮坂義浩、永井俊太郎、大塚隆生、中村雅史
  • Organizer: 第77回日本癌学会学術総会