Clarification and regulation of the involvement between BM-derived cells and pancreatic cancer clonality

• Project/Area Number: 18K16366
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyushu University
• Principal Investigator: Chika Iwamoto 九州大学, 大学病院, 特任助教 (10752842)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 膵癌 / 浸潤 / 癌

Outline of Final Research Achievements

In pancreatic ductal adenocarcinoma (PDAC), mesenchymal stem cells-derived tumor stroma seems to promote tumor development. However, involvement of bone marrow (BM)-derived cells on tumor progression and its mechanism remains unclear. We aimed to investigate an association between pancreatic cancer progression and BM-derived cells. In the pancreas of allogeneic models, GFP+BM-derived immune cells were accumulated at invasive front, and a few GFP+aSMA+ cells were detected. Some BM-derived cells interacted with pancreatic cancer cells (PCCs) expressed CAF markers. The heterogeneity of PCCs for PDAC development was investigated using whole exome sequencing. We identified the several organ-specific mutations.

Academic Significance and Societal Importance of the Research Achievements

膵癌細胞の刺激により骨髄由来細胞がCAFマーカーを発現することを新たに見出したことで、CAF のsubsetには様々な由来細胞が存在することが示唆された。由来細胞の同定は、膵癌微小環境におけるCAFの役割をより理解するためには必要不可欠であることから、本研究結果は学術的意義が高いと言える。また、転移形成において、臓器特異的な遺伝子変異が見られることが示唆された。臓器特異的転移形成の機序を解明することで、新たな治療法の開発に役立つと考えられる。これは、膵癌のみならず転移形成を生じる他の癌腫の治療にも応用できる可能性を秘めているため、社会的意義は大きいと言える。

Research Products

• [Journal Article] Establishment of a human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells (2020)
  • Author(s): Jinnouchi Fumiaki、Yamauchi Takuji、Yurino Ayano、Nunomura Takuya、Nakano Michitaka、Iwamoto Chika、Obara Teppei、Miyawaki Kohta、Kikushige Yoshikane、Kato Koji、Maeda Takahiro、Miyamoto Toshihiro、Baba Eishi、Akashi Koichi、Takenaka Katsuto
  • Journal Title: Blood Volume: - Issue: 19 Pages: 1661-1672
  • DOI: 10.1182/blood.2019002194
  • Peer Reviewed / Open Access
• [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] Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer-associated fibroblasts (2019)
  • Author(s): Takesue S、Ohuchida K、Shinkawa T、Otsubo Y、Matsumoto S、Sagara A、Yonenaga A、Ando Y、Kibe S、Nakayama H、Iwamoto C、Shindo K、Moriyama T、Nakata K、Miyasaka Y、Ohtsuka T、Toma H、Tominaga Y、Mizumoto K、Hashizume M、Nakamura M
  • Journal Title: International Journal of Oncology Volume: 56 Pages: 596-605
  • DOI: 10.3892/ijo.2019.4951
  • 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] Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer?stromal interaction and metastasis (2019)
  • Author(s): Yan Zilong、Ohuchida Kenoki、Fei Shuang、Zheng Biao、Guan Weiyu、Feng Haimin、Kibe Shin、Ando Yohei、Koikawa Kazuhiro、Abe Toshiya、Iwamoto Chika、Shindo Koji、Moriyama Taiki、Nakata Kohei、Miyasaka Yoshihiro、Ohtsuka Takao、Mizumoto Kazuhiro、Hashizume Makoto、Nakamura Masafumi
  • Journal Title: Journal of Experimental & Clinical Cancer Research Volume: 38 Issue: 1 Pages: 221-221
  • DOI: 10.1186/s13046-019-1226-8
  • Peer Reviewed / Open Access
• [Journal Article] Robust 3D image reconstruction of pancreatic cancer tumors from histopathological images with different stains and its quantitative performance evaluation. (2019)
  • Author(s): Kugler M, Goto Y, Tamura Y, Kawamura N, Kobayashi H, Yokota T, Iwamoto C, Ohuchida K, Hashizume M, Shimizu A, Hontani H.
  • Journal Title: Int J Comput Assist Radiol Surg Volume: 14 Issue: 12 Pages: 2047-2055
  • DOI: 10.1007/s11548-019-02019-8
  • Peer Reviewed / Open Access
• [Journal Article] Detection of pancreatic tumor cell nuclei via a hyperspectral analysis of pathological slides based on stain spectra (2019)
  • Author(s): Ishikawa Masahiro、Okamoto Chisato、Shinoda Kazuma、Komagata Hideki、Iwamoto Chika、Ohuchida Kenoki、Hashizume Makoto、Shimizu Akinobu、Kobayashi Naoki
  • Journal Title: Biomedical Optics Express Volume: 10 Issue: 9 Pages: 4568-4568
  • DOI: 10.1364/boe.10.004568
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma. (2018)
  • Author(s): K Koikawa, K Ohuchida, Y Ando, S Kibe, H Nakayama, S Takesue, S Endo, T Abe, T Okumura, C Iwamoto, T Moriyama, K Nakata, Y Miyasaka, T Ohtsuka, E Nagai, K Mizumoto, M Hashizume, M Nakamura.
  • Journal Title: Cancer Letters Volume: 425 Pages: 65-77
  • 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
• [Journal Article] Postmortem interval estimation using the animal model of postmortem gas volume changes. (2017)
  • Author(s): Iwamoto C, Ohuchida K, Okumura M, Usumoto Y, Kishimoto J, Murata M, Ikeda N, Hashizume M.
  • Journal Title: Legal Medicine Volume: - Pages: 66-70
  • DOI: 10.1016/j.legalmed.2017.12.010
  • Peer Reviewed / Open Access
• [Presentation] 膵癌微小環境下で骨髄造血幹細胞はCAF様の形態・機能を獲得し、膵癌の局所浸潤を誘導する (2020)
  • Author(s): 岩本千佳, 大内田研宙, 新川智彦, 大坪慶志輝, 奥田翔, 進藤幸治, 赤司浩一, 大塚隆生, 江藤正俊 中村雅史.
  • Organizer: 第75回日本消化器外科学会総会
• [Presentation] Human macrophages-derived CAF-like cells lead the invasion of pancreatic cancer. (2020)
  • Author(s): C Iwamoto, K Ohuchida, T Shinkawa, Y Ohtsubo, K Shindo, T Moriyama, K Nakata, T Ohtsuka, M Nakamura.
  • Organizer: 14th International Hepato-Pancreato-Biliary Association (IHPBA)
  • Int'l Joint Research
• [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回日本癌学会学術総会
• [Presentation] BM-derived Cells Destruct Basemen Membrane and Induce Local Invasion of Pancreatic Cancer. (2019)
  • Author(s): C Iwamoto, K Ohuchida, Y Ando, T Shinkawa, Y Ohtsubo, K Shindo, T Moriyama, K Nakata, K Miyawaki, T Ohtsuka, K Akashi, M Eto, M Nakamura.
  • Organizer: 50th Annual Meeting of the American Pancreatic Association
  • Int'l Joint Research
• [Presentation] Micro-CT in the Analysis of Formalin-Fixed Paraffin-embedded Blocks of Resected Pancreatic Lesions. (2019)
  • Author(s): K Shindo, K Ohuchida, H.R. Roth, H Oda, C Iwamoto, M Oda, T Ohtsuka, K Mori, M Hashizume, M Nakamura.
  • Organizer: 50th Annual Meeting of the American Pancreatic Association
  • Int'l Joint Research
• [Presentation] Repositioning of Duloxetine as a New Drug for Targeting Pancreatic Cancer Microenvironment. (2019)
  • Author(s): A Sagara, K Nakata, T Yamashita, W Guan, S Matsumoto, S Date, Y Ohtsubo, T Shinkawa, R Kimura, A Fujii, Y Ando, C Iwamoto, Y Watanabe, K Shindo, N Ikenaga, T Moriyama, K Ohuchida, T Ohtsuka, K Mizumoto, M Nakamura.
  • Organizer: 50th Annual Meeting of the American Pancreatic Association
  • Int'l Joint Research
• [Presentation] Accumulation and integration of various medical images derived from KPC mice and resected human pancreases. (2019)
  • Author(s): C Iwamoto, K Ohuchida, M Hashizume.
  • Organizer: 5th International Symposium on the Project “Multidisciplinary Computational Anatomy”
  • Int'l Joint Research
• [Presentation] Development of the novel prediction models using 3D-CT reconstructed images. (2019)
  • Author(s): K Shindo, K Ohuchida, C Iwamoto, HR. Roth, M Oda, K Mori, N Ikeda, M Hashizume.
  • Organizer: 5th International Symposium on the Project “Multidisciplinary Computational Anatomy”
  • Int'l Joint Research
• [Presentation] BM-derived Cells Differentiated into Multilineage Hematopoietic Cells Regulate Invasion and Proliferation of Pancreatic Cancer. (2018)
  • Author(s): C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, K Shindo, K Nakata, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.
  • Organizer: Pancreas 2018
  • Int'l Joint Research
• [Presentation] BM-derived cells recruited to the pancreas constitute the tumor microenvironment and promote invasion of pancreatic cancer. (2018)
  • Author(s): C Iwamoto, K Ohuchida, T Okumura, K Koikawa, S Takesue, H Nakayama, S Endo, S Kibe, Y Ando, K Miyawaki, M Murata, K Akashi, M Nakamura, M Hashizume.
  • Organizer: Digestive Disease Week
  • Int'l Joint Research
• [Presentation] 膵臓に誘導される骨髄由来細胞が癌微小環境を構成し膵癌浸潤を制御する (2018)
  • Author(s): 岩本千佳, 大内田研宙, 武居晋, 肥川和寛, 奥村隆志, 遠藤翔, 仲田興平, 宮脇恒太, 村田正治, 江藤正俊, 赤司浩一, 中村雅史, 橋爪誠.
  • Organizer: 第77回日本癌学会学術総会
• [Book] 「膵癌組織の病理像とMR像のデジタル画像統合と膵腫瘍微細構造解析」MEDICAL IMAGING TECHNOLOGY (2019)
  • Author(s): 岩本千佳, 大内田研宙, 橋爪誠
  • Total Pages: 207
  • Publisher: 学術新報社