The analyses of epithelial-mesenchymal transition associating with LIM protein family ZNF185 using in vivo liver metastasis mouse models of the human pancreas cancer.

• Project/Area Number: 16K07096
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Tokai University
• Principal Investigator: FURUKAWA Daisuke 東海大学, 医学部, 講師 (70459478)
• Co-Investigator(Kenkyū-buntansha): 平岡 伸介 国立研究開発法人国立がん研究センター, 中央病院, 科長 (40276217) ; 千々和 剛 自治医科大学, 医学部, 講師 (70642180) ; 河村 大輔 東京大学, 大学院医学系研究科(医学部), 助教 (10776082) ; 鈴木 涼平 自治医科大学, 医学部, 助教 (30621809)
• Research Collaborator: NAKAMURA Masato 東海大学, 医学部, 教授 (00164335)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ZNF185 / 膵癌 / PDX / インタラクト―ム / インタラクトーム / 上皮間葉転換

Outline of Final Research Achievements

In this study, we analyzed the molecular biology of human pancreatic ductal carcinoma (PDC) during hematogenous metastasis using the experimental liver metastasis mice models. The membranous expression of ZNF185 at the periphery of cancer cell nests was an independent indicator of unfavorable prognosis in patients with PDC. We also performed interactome analyses using patient-derived xenograft (PDX) of PDC. Interactome analyses disclosed interactions between PDC cells and stroma and they were genomically diverse, thus the personalized medicine
using PDX is suitable for PDC. During the PDX establishment process, the occurrence of transplantable lymphoproliferative lesion (LPL) that replaces the original tumor cells is the most problematic aspect. In our interactome results, LPLs occur due to a lymphotoxin-alpha-related mechanism. Controlling lymphotoxin-alpha related interactions by FK506 can suppress LPL and improve the establishment rate of PDX for personalized medicine of PDC.

Academic Significance and Societal Importance of the Research Achievements

膵癌は早期に遠隔転移する難治性腫瘍の代表であり、転移性膵癌に対する有効な治療が求められている。我々が発見し、臨床的に確認した腫瘍先端部におけるZNF185細胞膜発現パターンが腫瘍浸潤能を示すマーカーであることは今後の膵癌の治療法決定に役立つものと考えられる。一方で膵癌相互作用プロファイルは非常に多様性があり、画一的な治療では成績向上は困難であり、即ち個別化医療の良い適応となると考えられる。今回の研究成果は個別化医療に対応するPDXを効率的に樹立する点においても有用な結果が得られた。本研究は、PDXを用いた膵癌転移・浸潤機構のZNF185解析による個別化医療を実現させる可能性を示すものである

Research Products

• [Journal Article] Plasma membrane expression of ZNF185 is a prognostic factor in pancreatic ductal carcinoma (2017)
  • Author(s): Furukawa Daisuke、Chijiwa Tsuyoshi、Matsuyama Masahiro、Mukai Masaya、Matsuo Ei-Ichi、Nishimura Osamu、Kawai Kenji、Suemizu Hiroshi、Nakagohri Toshio、Ozawa Soji、Shimada Kazuaki、Hiraoka Nobuyoshi、Nakamura Masato
  • Journal Title: Oncology Letters Volume: 14 Issue: 3 Pages: 3633-3640
  • DOI: 10.3892/ol.2017.6633
  • Peer Reviewed / Open Access
• [Presentation] Lymphotoxin-alpha plays key roles in lymphoproliferative lesions arising in patient-derived cancer (2018)
  • Author(s): TSUYOSHI CHIJIWA, DAISUKE KOMURA, MIZUHA HARAGUCHI, HARUO HASHIMOTO, HIROSHI SUEMIZU, MAKOTO KATAYAMA, YOSHIYASU NAKAMURA, DAISUKE FURUKAWA, TAKAYUKI ISAGAWA, HIROTO KATO, TAKASHI MORIYA, SHUMPEI ISHIKAWA, MASATO NAKAMURA, YOHEI MIYAGI
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] An interactome analysis for personalized chemotherapy using PDX/NOG models of non-small cell lung cancer (2017)
  • Author(s): Chijiwa T, Komura D, Haraguchi M, Noguchi A, Sato H, Ito H, Nakayama H, Katayama M, Miyao N, Matsui N, Tateishi Y, Suemizu H, Nakamura Y, Furukawa D, Isagawa T, Katoh H, Moriya T, Ishikawa S, Nakamura M, Miyagi Y
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] The prevention of lymphoproliferative lesions arising in patient-derived cancer enografts by anti-graft-versus-host-disease agents (2017)
  • Author(s): Chijiwa T, Noguchi A, Komura D, Katayama M, Haraguchi M, Hashimoto H, Suemizu H, Nakamura Y, Furukawa D, Isagawa T, Katoh H, Moriya T, Ishikawa S, Nakamura M, Miyagi Y
  • Organizer: AACR Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond
  • Int'l Joint Research
• [Presentation] The possibility of personalized chemotherapy for non-small cell lung cancer using interactome analyses of PDX/NOG models (2017)
  • Author(s): Chijiwa T, Komura D, Haraguchi M, Noguchi A, Sato H, Ito H, Nakayama H, Katayama M, Miyao N, Suemizu H, Nakamura Y, Furukawa D, Moriya T, Isagawa T, Katoh H, Ishikawa S, Nakamura M, Miyagi Y
  • Organizer: ESMO Asia 2017
  • Int'l Joint Research
• [Presentation] Zinc finger protein 185 is a key molecule of liver metastasis in colon cancer. (2016)
  • Author(s): Furukawa D, Chijiwa T, Matsuyama M, Mukai M, Matsuo E, Nishimura O, Kawai K, Suemizu H, Nakagohri T, Yasuda S, Shimada K, Hiraoka N, Nakamura M.
  • Organizer: AACR Anual Meeting 2016
  • Place of Presentation: Ernest N. Morial Convention Center New Orleans
  • Year and Date: 2016-04-16
  • Int'l Joint Research