Systemic generation of metastatic models of lung adenocarcinoma

• Project/Area Number: 25670178
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: Jichi Medical University
• Principal Investigator: niki toshiro 自治医科大学, 医学部, 教授 (90198424)
• Co-Investigator(Kenkyū-buntansha): YOSHIMOTO TAICHIRO 自治医科大学, 医学部, 講師 (20634166)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺癌 / 転移 / マウス

Outline of Final Research Achievements

In this study, we established a series of mouse models of lung cancer metastasis by intracardiac inoculation of lung adenocarcinoma cell lines harboring various driver mutations, such as EGFR, KRAS, ALK, and MET. We also generated subclones that has the ability to grow in suspended condition but reattach in ordinary culture, by long-term, 3-dimensional culture under low-bind culture conditions. These subclones, designated FL clones, exhibited highly metastatic potential as compared to parental cell lines. We further performed comprehensive genomic analysis of the cell lines (parental and FL cell lines) and identified metastasis-related genes that showed altered expression in FL cells vs. parental cells, and genomic regions amplified in FL cell lines. Thus, the metastatic models created in the present study would be a promising new resource to study the molecular mechanisms of lung cancer metastasis that develop under various genetic background.

Research Products

• [Journal Article] Prolyl isomerase Pin1 promotes survival in EGFR-mutant lung adenocarcinoma cells with an epithelial-mesenchymal transition phenotype. (2016)
  • Author(s): Sakuma Y, Nishikiori H, Hirai S, Yamaguchi M, Yamada G, Watanabe A, Hasegawa T, Kojima T, Niki T, Takahashi H.
  • Journal Title: Lab Invest. Volume: 96 Issue: 4 Pages: 391-398
  • DOI: 10.1038/labinvest.2015.155
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Frequent loss of the expression of multiple subunits of the SWI/SNF complex in large cell carcinoma and pleomorphic carcinoma of the lung. (2015)
  • Author(s): Yoshimoto T, Matsubara D, Nakano T, Tamura T, Endo S, Sugiyama Y, Niki T.
  • Journal Title: Pathology international Volume: 35 Issue: 11 Pages: 595-602
  • DOI: 10.1111/pin.12350
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The role of HGF/MET and FGF/FGFR in fibroblast-derived growth stimulation and lapatinib-resistance of esophageal squamous cell carcinoma (2015)
  • Author(s): Shin Saito, Kazue Morishima, Takashi Ui, Hiroko Hoshino, Daisuke Matsubara, Shumpei Ishikawa, Hiroyuki Aburatani, Masashi Fukayama, Yoshinori Hosoya, Naohiro Sato, Alan K Lefor, Yoshikazu Yasuda and Toshiro Niki
  • Journal Title: BMC cancer Volume: 15 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s12885-015-1065-8
  • Peer Reviewed / Open Access
• [Journal Article] The HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway. (2014)
  • Author(s): Ui T, Morishima K, Saito S, Sakuma Y, Fujii H, Hosoya Y, Ishikawa S, Aburatani H, Fukayama M, Niki T, Yasuda Y.
  • Journal Title: Oncol Rep. Volume: 31(2) Issue: 2 Pages: 619-24
  • DOI: 10.3892/or.2013.2899
  • Peer Reviewed / Open Access
• [Journal Article] Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. (2014)
  • Author(s): Ibrahim R, Matsubara D, Osman W, Morikawa T, Goto A, Morita S, Ishikawa S, Aburatani H, Takai D, Nakajima J, Fukayama M, Niki T, Murakami Y
  • Journal Title: Hum Pathol. Volume: 45 Issue: 7 Pages: 1397-405
  • DOI: 10.1016/j.humpath.2014.02.013
  • Peer Reviewed / Open Access
• [Journal Article] Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma. (2014)
  • Author(s): Saito S, Morishima K, Ui T, Matsubara D, Tamura T, Oguni S, Hosoya Y, Sata N, Lefor AT, Yasuda Y, Niki T.
  • Journal Title: Oncology Reports Volume: 32 Issue: 1 Pages: 348-354
  • DOI: 10.3892/or.2014.3216
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical analysis of the expression of E-cadherin and ZEB1 in non-small cell lung cancer. (2014)
  • Author(s): Matsubara D, Kishaba Y, Yoshimoto T, Sakuma Y, Sakatani T, Tamura T, Endo S, Sugiyama Y, Murakami Y, Niki T
  • Journal Title: Pathology International Volume: 64 Issue: 11 Pages: 560-568
  • DOI: 10.1111/pin.12214
  • Peer Reviewed / Open Access
• [Journal Article] Lung cancer with loss of BRG1?BRM,shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. (2013)
  • Author(s): Matsubara D, Murakami Y, Niki T et al.
  • Journal Title: Cancer Sci Volume: 104 Issue: 2 Pages: 266-273
  • DOI: 10.1111/cas.12065
  • Peer Reviewed
• [Journal Article] Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells. (2013)
  • Author(s): Sakuma Y, Matsukuma S, Nakamura Y, Yoshihara M, Koizume S, Sekiguchi H, Saito H, Nakayama H, Kameda Y, Yokose T, Oguni S, Niki T, and Miyagi Y.
  • Journal Title: Lab Invest. Volume: 93 Issue: 10 Pages: 1137-1146
  • DOI: 10.1038/labinvest.2013.102
  • Peer Reviewed
• [Presentation] CADM1陽性の高悪性度肺腺癌におけるRAPGEF2の役割． (2015)
  • Author(s): 許淑真，松原大祐，森川鉄平，中島淳，深山正久，仁木利郎，村上善則
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 肺癌におけるYAP1 欠如と神経内分泌分化について (2015)
  • Author(s): 松原大祐，伊東剛，田中一大，石川俊平，後藤悌，中野智之，土橋洋，中島淳，遠藤俊輔，深山正久，関戸好孝，仁木利郎，村上善則
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Altered expressions of multiple subunits of the switch/sucrose non-fermenting (SWI/SNF) complex in Non-small cell lung cancer. (2015)
  • Author(s): Yoshimoto T, Matsubara D, Niki T.
  • Organizer: AACR special meeting
  • Place of Presentation: Atlanta
  • Year and Date: 2015-09-24
• [Presentation] Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. (2014)
  • Author(s): Matsubara D, Ibrahim R, Osman W, Goto A, Morikawa T, Morita S, Ishikawa S, Aburatani H, Fukayama M, Niki T, Murakami Y.
  • Organizer: Annual Meeting of American Association for Cancer Research
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] The HSP90 inhibitor 17-AAG improves chemoresistance of cisplatin-resistant esophageal squamous cell carcinoma cell lines. (2014)
  • Author(s): Ui T, Morishima K, Saito S, Sakuma Y, Fujii H, Hosoya Y, Yasuda Y, Niki T.
  • Organizer: Annual Meeting of American Association for Cancer Research
  • Place of Presentation: San Diego
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Molecular mechanisms for EMT in lung cancer; relationship with chromatin remodeling factors and mutation of EGFR. (2013)
  • Author(s): Yoshimoto T, Niki T, Matsubara D.
  • Organizer: 72th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] RET融合遺伝子を有する肺腺癌細胞株の発見 (2013)
  • Author(s): 松原大祐、石川俊平、小原詩織、吉本多一郎、坂谷貴司、片岡寛章、村上善則、油谷浩幸、深山正久、仁木利郎．
  • Organizer: 日本病理学会
  • Place of Presentation: 札幌
• [Remarks] 自治医科大学統合病理学部門ホームページ
  • URL: http://www.jichi.ac.jp/pathol/