Roles of TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma

• Project/Area Number: 25250017
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Nagoya University
• Principal Investigator: Takahashi Takashi 名古屋大学, 医学(系)研究科(研究院), 教授 (50231395)
• Co-Investigator(Kenkyū-buntansha): MIYANO Satoru 東京大学, 医科学研究所, 教授 (50128104) ; YANAGISAWA Kiyoshi 名古屋大学, 大学院医学系研究科, 講師 (20372112)
• Co-Investigator(Renkei-kenkyūsha): ASAI Naoya 名古屋大学, 大学院医学系研究科, 准教授 (80273233)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥46,410,000 (Direct Cost: ¥35,700,000、Indirect Cost: ¥10,710,000); Fiscal Year 2015: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2014: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2013: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
• Keywords: 癌 / シグナル伝達 / システム生物学 / がん遺伝子

Outline of Final Research Achievements

This study has demonstrated that ROR plays a crucial role as a “sustainer” receptor tyrosine kinase (RTK) in the molecular pathogenesis of lung adenocarcinoma through establishment of Ror1 conditional knockout mice exhibiting mutant EGFR-driven tumorigenesis. We have also found that ROR1 sustains survival signaling of multiple RTKs by maintaining CAV1 expression and caveolae structure. Finally, a novel gene, MXTN, modulating TTF-1-mediated transcriptional regulation, was identified through a combined approach employing both systems biologic and cancer biologic analyses.

Research Products

• [Journal Article] ROR1 sustains caveolae and survival signaling as a scaffold of cavin-1 and caveolin-1 (2016)
  • Author(s): Yamaguchi T, Lu C, Yanagisawa K, Can Lu, Usukura J, Cheng J, Hotta N, Shimada Y, Ida R, Isomura H, Suzuki M, Fujimoto T, Takahashi T
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 10060-10060
  • DOI: 10.1038/ncomms10060
  • Peer Reviewed / Open Access
• [Journal Article] Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells. (2016)
  • Author(s): Suzuki M, et al.
  • Journal Title: J. Clin. Invest. Volume: 126 Issue: 1 Pages: 254-265
  • DOI: 10.1172/jci79775
  • Peer Reviewed / Open Access
• [Journal Article] Receptor tyrosine kinase-like orphan receptor 1, a target of NKX2-1/TTF-1 lineage-survival oncogene, inhibits apoptosis signal-regulating kinase 1-mediated pro-apoptotic signaling in lung adenocarcinoma (2016)
  • Author(s): Ida L, Yamaguchi T, Yanagisawa K, Kajino T, Shimada Y, Suzuki M, Takahashi T
  • Journal Title: Cancer Sci Volume: 107 Issue: 2 Pages: 155-161
  • DOI: 10.1111/cas.12858
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gene set differential analysis of time course expression profiles via sparse estimation in functional logistic model with application to time-dependent biomarker detection (2016)
  • Author(s): Kayano M, Matsui H, Yamaguchi R, Imoto S, Miyano S
  • Journal Title: Biostatistics Volume: 17 Issue: 2 Pages: 235-248
  • DOI: 10.1093/biostatistics/kxv037
  • Peer Reviewed
• [Journal Article] miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer. (2015)
  • Author(s): Tai MC, Kajino T, Nakatochi M, Arima C, Shimada Y, Suzuki M, Miyoshi H, Yatabe Y, Yanagisawa K, Takahashi T.
  • Journal Title: Carcinogenesis Volume: 36 Pages: 1464-1473
  • DOI: 10.1093/carcin/bgv152
  • Peer Reviewed
• [Journal Article] Genomon ITDetector: a tool for somatic internal tandem duplication detection from cancer genome sequencing data. (2015)
  • Author(s): Chiba K, Shiraishi Y, Nagata Y, Yoshida K, Imoto S, Ogawa S, Miyano S.
  • Journal Title: Bioinformatics Volume: 31 Issue: 1 Pages: 116-118
  • DOI: 10.1093/bioinformatics/btu593
  • Peer Reviewed
• [Journal Article] Probabilistic expression of spatially varied amino acid dimers into general form of Chou's pseudo amino acid composition for protein fold recognition (2015)
  • Author(s): Saini H, Raicar G, Sharma A, Lal S, Dehzangi A, Lyons J, Paliwal KK, Imoto S, Miyano S
  • Journal Title: J Theor Biol Volume: 380 Pages: 291-298
  • DOI: 10.1016/j.jtbi.2015.05.030
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features (2014)
  • Author(s): Arima C, Kajino T, Tamada Y, Imoto S, ShimadaY, Nakatochi, M, Suzuki M, Isomura H, Yatabe Y, Yamaguchi T, Yanagisawa K, Miyano S, Takahashi T
  • Journal Title: Carcinogenesis Volume: 35 Issue: 10 Pages: 2224-2231
  • DOI: 10.1093/carcin/bgu127
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CSML2SBML: a novel tool for converting quantitative biological pathway models from CSML into SBML (2014)
  • Author(s): Li C, Nagasaki M, Ikeda E, Sekiya Y, Miyano S.
  • Journal Title: Biosystems Volume: 121 Pages: 402-414
  • DOI: 10.1016/j.biosystems.2014.05.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation (2014)
  • Author(s): Shinjo K, Yamashita Y, Yamamoto E, Akatsuka S, Uno N, Kamiya A, Niimi K, Sakaguchi Y, Nagasaka T, Takahashi T, Shibata K, Kajiyama H, Kikkawa F, Toyokuni S
  • Journal Title: Int J Cancer Volume: 135 Issue: 2 Pages: 308-318
  • DOI: 10.1002/ijc.28692
  • Peer Reviewed
• [Journal Article] Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib (2014)
  • Author(s): Younes M, Wu Z, Dupouy S, Lupo AM, Mourra N, Takahashi T, Flejou JF, Tredaniel J, Regnard JF, Damotte D, Alifano M, Forgez P
  • Journal Title: Oncotarget Volume: 5 Issue: 18 Pages: 8252-8269
  • DOI: 10.18632/oncotarget.1633
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor-derived Interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages (2014)
  • Author(s): Watari K, Shibata T, Kawahara A, Sata K, Nabeshima H, Shinoda A, Abe H, Azuma K, Murakami Y, Izumi, H, Takahashi T, Kage M, Kuwano M, Ono M.
  • Journal Title: PLoS ONE Volume: 9 Issue: 6 Pages: e99568-e99568
  • DOI: 10.1371/journal.pone.0099568
  • Peer Reviewed / Open Access
• [Journal Article] HapMuC: somatic mutation calling using heterozygous germ line variants near candidate mutations (2014)
  • Author(s): Usuyama N, Shiraishi Y, Sato Y, Kume H, Homma Y, Ogawa S, Miyano S, Imoto S
  • Journal Title: Bioinformatics Volume: 30 Issue: 23 Pages: 3302-3309
  • DOI: 10.1093/bioinformatics/btu537
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production (2013)
  • Author(s): S. H. Chew, Y. Okazaki, H. Nagai, N. Misawa, S. Akatsuka, K. Yamashita, L. Jiang, Y. Yamashita, M. Noguchi, K. Hosoda, Y. Sekido, T. Takahashi, S. Toyokuni
  • Journal Title: Carcinogenesis Volume: 35(1) Issue: 1 Pages: 164-172
  • DOI: 10.1093/carcin/bgt267
  • Peer Reviewed / Open Access
• [Journal Article] NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression (2013)
  • Author(s): Yamaguchi T, Hosono Y, Yanagisawa K, Takahashi T
  • Journal Title: Cancer Cell Volume: 23 Issue: 6 Pages: 718-723
  • DOI: 10.1016/j.ccr.2013.04.002
  • Peer Reviewed
• [Journal Article] Quantitative proteomic profiling identifies DPYSL3 as pancreatic ductal adenocarcinoma-associated molecule that regulates cell adhesion and migration by stabilization of focal adhesion complex (2013)
  • Author(s): Kawahara T, Hotta N, Ozawa Y, Kato S, Kano K, Yokoyama Y, Nagino M, Takahashi T, Yanagisawa K
  • Journal Title: PLoS ONE Volume: 8 Issue: 12 Pages: e79654-e79654
  • DOI: 10.1371/journal.pone.0079654
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibitory effects of salinomycin on cell survival, colony growth, migration, and invasion of human non-small cell lung cancer A549 and LNM35: Involvement of NAG-1 (2013)
  • Author(s): Arafat K, Iratni R, Takahashi T, Parekh K, Al Dhaheri Y, Adrian TE, Attoub S.
  • Journal Title: PLoS ONE Volume: 8 Issue: 6 Pages: e66931-e66931
  • DOI: 10.1371/journal.pone.0066931
  • Peer Reviewed / Open Access
• [Journal Article] Thymoquinone as an anticancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo (2013)
  • Author(s): Attoub S, Sperandio O, Raza H, Arafat K, Al-Salam S, Al Sultan MA, Al Safi M, Takahashi T, Adem A
  • Journal Title: Fundam Clin Pharmacol Volume: 27 Issue: 5 Pages: 557-569
  • DOI: 10.1111/j.1472-8206.2012.01056.x
  • Peer Reviewed
• [Journal Article] Cytotoxic interaction between amiodarone and desethylamiodarone in human peripheral lung epithelial cells (2013)
  • Author(s): Roth FC, Mulder JE, Brien JF, Takahashi T, Massey TE
  • Journal Title: Chem Biol Interact Volume: 204 Issue: 3 Pages: 135-139
  • DOI: 10.1016/j.cbi.2013.05.006
  • Peer Reviewed
• [Journal Article] SGOL1 variant B induces abnormal mitosis and resistance to taxane in non-small cell lung cancers (2013)
  • Author(s): Matsuura S, Kahyo T, Shinmura K, Iwaizumi M, Yamada H, Funai K, Kobayashi J, Tanahashi M, Niwa H, Ogawa H, Takahashi T, Inui N, Suda T, Chida K, Watanabe Y, *Sugimura H.
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 3012-3012
  • DOI: 10.1038/srep03012
  • Peer Reviewed / Open Access
• [Journal Article] Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis (2013)
  • Author(s): Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, Kajiyama H, Kikkawa F, Takahashi T, Toyokuni S
  • Journal Title: PLoS ONE Volume: 8 Issue: 3 Pages: e57724-e57724
  • DOI: 10.1371/journal.pone.0057724
  • Peer Reviewed / Open Access
• [Presentation] 肺癌の発生と進展の分子機構の解明：基礎研究のこれまでとこれから (2015)
  • Author(s): 高橋隆
  • Organizer: 第56回日本肺癌学会学術集会
  • Place of Presentation: パシフィコ横浜 （神奈川県横浜市）
  • Year and Date: 2015-11-26
  • Invited
• [Presentation] Identification of non-coding RNAs modulating MYC activity in human lung cancers (2015)
  • Author(s): Takahashi T
  • Organizer: The 74th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] ROR1 functions as a scaffold of cavin-1 and CAV1, sustaining caveolae and RTK-mediated survival signaling in lung cancer (2015)
  • Author(s): 3Yamaguchi T, Yanagisawa K, Lu C, Ida L, Isomura H, Suzuki M, Fujimoto T, Takahashi T
  • Organizer: The 74th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] ROR1, a transcriptional target of TTF-1/NKX2-1 oncogene, sustains lineage-survival signaling in lung adenocarcinoma (2014)
  • Author(s): Takahashi T
  • Organizer: Japanese-German Cancer Workshop
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2014-11-14
  • Int'l Joint Research / Invited
• [Presentation] Elucidation of transcriptional regulatory circuitry involved in the molecular pathogenesis of lung cancer (2014)
  • Author(s): Takahashi T
  • Organizer: The Japanese Cancer Association
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25
  • Invited
• [Presentation] TTF-1/NKX2-1: an enigmatic oncogene that functions as a double-edged sword in lung adenocarcinoma (2013)
  • Author(s): Takahashi T
  • Organizer: SNUCRI & SNUCH Cancer Symposium
  • Place of Presentation: Jeju, Korea
  • Invited
• [Presentation] Multifaceted dissection of genetic regulatory circuitry involved in the pathogenesis of lung cancers (2013)
  • Author(s): Takahashi T
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Invited
• [Presentation] Targeting ceramide homeostasis and metastasis-prone phenotypes in human lung cancer cells (2013)
  • Author(s): Motoshi Suzuki, Seiichi Kato, Yuji Komizu, Ryuichi Ueoka, Chinatsu Arima, Kiyoshi Yanagisawa, Keiko Tamiya-Koizumi, Takashi Murate, Mamoru Kyogashima and Takashi Takahashi
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] Proteomic identification of potential biomarkers of human lung malignancies (2013)
  • Author(s): Yanagisawa K, Takahashi T
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Invited
• [Remarks] 名古屋大学大学院医学系研究科分子腫瘍学分野
  • URL: http://www.med.nagoya-u.ac.jp/molcar/jp/research.html
• [Remarks] 分子腫瘍学分野 研究テーマ
  • URL: http://www.med.nagoya-u.ac.jp/molcar/jp/research.html
• [Patent(Industrial Property Rights)] 癌細胞のカベオラの形成を特異的に抑制する化合物のスクリーニング方法、スクリーニングキット、該キットに用いるベクター及び形質転換体、並びに分子標的薬の適応患者の選択方法 (2014)
  • Inventor(s): 高橋隆、山口知也
  • Industrial Property Rights Holder: 国立大学法人名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-10-24
  • Overseas