HOME > Members > GCOE Organizing Members > Takashi Takahashi MD, PhD


Takashi Takahashi MD, PhDProfessor, Department of Molecular Carcinogenesis, Nagoya University Graduate School of Medicine


Specialized field

Medical Oncology

Career Summary

Education and Training:

1979
M.D. (Nagoya University School of Medicine)
1988
Ph.D. (Nagoya University)
1988-2000
Research Fellow, Aichi Cancer Center Research Institute
1988-1990
Postdoctoral Fellow, NCI-Navy Medical Oncology Branch, NCI

Positions Held:

1979-1984
Residency and clinical training (Surgery)
1990-1995
Laboratory of Chemotherapy, Aichi Cancer Center Research Institute
1995-2000
Chief, Laboratory of Ultrastructure Research, Aichi Cancer Center
2000-2004
Chief, Division of Molecular Oncology, Aichi Cancer Center
2004-present
Professor, Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine

Research Theme

Multidirectional dissection of molecular pathogenesis of human solid tumors

Research Summary

Multi-directional dissection of the molecular pathogenesis of human solid tumors

This research project aims at gaining insight into the molecular mechanisms underlying human carcinogenesis and progression, especially those of lung cancer, through a wide range of basic and applied experimental findings, as well as molecular correlative studies. Multi-directional dissection including gene and protein expression profiling strategies are being employed for better understanding of the molecular pathogenesis in line with realization of our major objective, "from bench to bedside". It is well understood that oncogene addiction is present in certain cancers, with lung adenocarcinomas carrying epidermal growth factor receptor (EGFR) mutations among the best examples. Emerging evidence, though currently sparse, suggests that “lineage-specific transcription factors” with developmental roles in normal progenitor cells of particular lineages may also confer dependency for survival to certain types of cancer cells. TTF-1, a homeodomain transcription factor also known as NKX2-1 and TTF-1, plays essential roles in peripheral lung development, and TTF-1 deficiency in mice results in lung aplasia. We previously reported that TTF-1 is a reliable lineage marker for terminal respiratory unit (TRU) cells, as well as for “TRU-type” adenocarcinomas with distinct gene expression profiles, which show abundant TTF-1 expression as well as characteristic clinicopathologic and genetic features including a significant association with EGFR mutations. We further identified TTF-1 as a lineage-survival oncogene in lung adenocarcinoma (Tanaka H et al, Cancer Res 2007), other investigators reached similar conclusions through genome-wide searches for focal genomic aberrations. In this study, we have found that TTF-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and proapoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. From a clinical point of view, it is thus of particular interest that ROR1 inhibition appears to be effective for treatment of gefitinib-resistant lung adenocarcinomas with various resistance mechanisms. Our findings thus identify ROR1 as an “Achilles’ heel” in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer (Yamaguchi T, et al, Cancer Cell 2012). Cell migration driven by actomyosin filament assembly is a critical step in tumor invasion and metastasis. We have also identified myosin binding protein H (MYBPH) as a transcriptional target of TTF-1, a master regulator of lung development that also plays a role as a lineage-survival oncogene via the induction of ROR1 as described above. MYBPH inhibited assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK), through its direct physical interaction with Rho kinase 1 (ROCK1) rather than Rho kinase 2 (ROCK2). Consequently, MYBPH inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of TTF-1-positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of TTF-1 expression with favorable prognosis in lung adenocarcinoma patients (Hosono Y, et al, EMBO J, 2012).

Principal Research Achievement

  1. Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, Kato S, Tomida S, Suzuki M, Osada H, Takahashi T: NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma. Cancer Cell, 21, 348-361 (2012)
  2. Endo M, Nakano M, Kadomatsu T, Fukuhara S, Kuroda H, Mikami S, Hato T, Aoi J, Horiguchi H, Miyata K, Odagiri H, Masuda T, Harada M, Horio H, Hishima T, Nomori H, Ito T, Yamamoto Y, Minami T, Okada S, Takahashi T, Mochizuki N, Iwase H, Oike Y: Tumor Cell-Derived Angiopoietin-like Protein ANGPTL2 Is a Critical Driver of Metastasis. Cancer Res, 72, 1784-1794 (2012)
  3. Hosono Y, Yamaguchi T, Mizutani E, Yanagisawa K, Arima C, Tomida S, Shimada Y, Hiraoka M, Kato S, Yokoi K, Suzuki M, Takahashi T: MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis. Embo J, 31, 481-493 (2012)
  4. Attoub S, Hassan AH, Vanhoecke B, Iratni R, Takahashi T, Gaben AM, Bracke M, Awad S, John A, Kamalboor HA, Al Sultan MA, Arafat K, Gespach C, Petroianu G: Inhibition of cell survival, invasion, tumor growth and histone deacetylase activity by the dietary flavonoid luteolin in human epithelioid cancer cells. Eur J Pharmacol, 651, 18-25 (2011)
  5. Matsuyama Y, Suzuki M, Arima C, Huang QM, Tomida S, Takeuchi T, Sugiyama R, Itoh Y, Yatabe Y, Goto H, Takahashi T: Proteasomal non-catalytic subunit PSMD2 as a potential therapeutic target in association with various clinicopathologic features in lung adenocarcinomas. Mol Carcinog, 50, 301-309 (2011)
  6. Mulder JE, Brien JF, Racz WJ, Takahashi T, Massey TE: Mechanisms of amiodarone and desethylamiodarone cytotoxicity in nontransformed human peripheral lung epithelial cells. J Pharmacol Exp Ther, 336, 551-559 (2011)
  7. Nishikawa E, Osada H, Okazaki Y, Arima C, Tomida S, Tatematsu Y, Taguchi A, Shimada Y, Yanagisawa K, Yatabe Y, Toyokuni S, Sekido Y, Takahashi T: miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. Cancer Res, 71, 6165-6173 (2011)
  8. Shimamura T, Imoto S, Shimada Y, Hosono Y, Niida A, Nagasaki M, Yamaguchi R, Takahashi T, Miyano S: A novel network profiling analysis reveals system changes in epithelial-mesenchymal transition. PLoS One, 6, e20804 (2011)
  9. Sides MD, Klingsberg RC, Shan B, Gordon KA, Nguyen HT, Lin Z, Takahashi T, Flemington EK, Lasky JA: The Epstein-Barr virus latent membrane protein 1 and transforming growth factor--beta1 synergistically induce epithelial--mesenchymal transition in lung epithelial cells. Am J Respir Cell Mol Biol, 44, 852-862 (2011)
  10. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D: International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol, 6, 244-285 (2011)
  11. Miki D, Kubo M, Takahashi A, Yoon KA, Kim J, Lee GK, Zo JI, Lee JS, Hosono N, Morizono T, Tsunoda T, Kamatani N, Chayama K, Takahashi T, Inazawa J, Nakamura Y, Daigo Y: Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat Genet, 42, 893-896 (2010)
  12. Huang QM, Akashi T, Masuda Y, Kamiya K, Takahashi T, Suzuki M: Roles of POLD4, smallest subunit of DNA polymerase delta, in nuclear structures and genomic stability of human cells. Biochem Biophys Res Commun, 391, 542-546 (2010)
  13. Heishi T, Hosaka T, Suzuki Y, Miyashita H, Oike Y, Takahashi T, Nakamura T, Arioka S, Mitsuda Y, Takakura T, Hojo K, Matsumoto M, Yamauchi C, Ohta H, Sonoda H, Sato Y: Endogenous angiogenesis inhibitor vasohibin1 exhibits broad-spectrum antilymphangiogenic activity and suppresses lymph node metastasis. Am J Pathol, 176, 1950-1958 (2010)
  14. Alifano M, Souaze F, Dupouy S, Camilleri-Broet S, Younes M, Ahmed-Zaid SM, Takahashi T, Cancellieri A, Damiani S, Boaron M, Broet P, Miller LD, Gespach C, Regnard JF, Forgez P: Neurotensin receptor 1 determines the outcome of non-small cell lung cancer. Clin Cancer Res, 16, 4401-4410 (2010)
  15. Bryant CM, Albertus DL, Kim S, Chen G, Brambilla C, Guedj M, Arima C, Travis WD, Yatabe Y, Takahashi T, Brambilla E, Beer DG: Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study. PLoS One, 5, e11712 (2010)
  16. Tanaka S, Cao K, Niimi A, Limsirichaikul S, Huang QM, Nakamura N, Murate T, Hasegawa Y, Takahashi T, Suzuki M. Functions of base selection step in human DNA polymerase alpha. DNA Repair, 9, 534-541 (2010).
  17. Hu Q, Akatsuka S, Yamashita Y, Ohara H, Nagai H, Okazaki Y, Takahashi T, Toyokuni S. Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma. Lab Invest, 90, 360-373 (2010)
  18. Tomida S, Takeuchi T, Shimada Y, Arima C, Matsuo K, Mitsudomi T, Yatabe Y, Takahashi T. Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis. J Clin Oncol, 27, 2793-2799 (2009)
  19. Ebi H, Tomida S, Takeuchi T, Arima C, Sato T, Mitsudomi T, Yatabe Y, Osada H, Takahashi T. Relationship of deregulated signaling converging onto mTOR with prognosis and classification of lung adenocarcinoma shown by two independent in silico analyses. Cancer Res, 69, 4027-4035 (2009)
  20. Ebi H, Sato T, Sugito N, Hosono Y, Suzuki M, Yamaguchi T, Yatabe Y, Osada H, Takahashi T. Counterbalancing influence of miR-17-92 overexpression on adverse effects of RB inactivation in lung cancers. Oncogene, 28, 3371-3379 (2009)
  21. Suzuki M, Niimi A, Limsirichaikul S, Tomida S, Huang QM, Izuta S, Usukura J, Itoh Y, Hishida T, Akashi T, Nakagawa Y, Kikuchi A, Pavlov Y, Murate T, Takahashi T. PCNA Mono-ubiquitination and Activation of Translesion DNA Polymerases by DNA Polymerase α. J Biochem, 146, 13-21 (2009)
  22. Yazawa T, Sato H, Shimoyamada H, Okudela K, Woo H, Tajiri M, Ogura T, Ogawa N, Suzuki T, Mitsui H, Ishii J, Miyata C, Sakaeda M, Goto K, Kashiwagi K, Masuda M, Takahashi T, Kitamura H. Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer. Am J Pathol, 175, 976-987 (2009)
  23. Okudera K, Yazawa T, Woo T, Sakaeda M, Ishii J, Mitsui H, Tajiri M, Ogawa N, Masuda M, Takahashi T, Sugimura H, Kitamura H. Down-regulation of DUSP6 expression in lung cancers: its mechanism and potential role in carcinogenesis. Am J Pathol, 175, 867-881 (2009)
  24. Taguchi A, Yanagisawa K, Tanaka M, Cao K, Matsuyama Y, Goto H, Takahashi T. Identification of HIF-1a as a novel target for miR-17-92 microRNA cluster. Cancer Res, 68, 5540-5545 (2008)
  25. Osada H, Tomida S, Yatabe Y, Tatematsu Y, Takeuchi T, Murakami H, Kondo Y, Sekido Y, Takahashi T. Roles of ASH1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. Cancer Res, 68, 1647-1655 (2008)
  26. Tokumaru S, Suzuki M, Yamada H, Nagino N, Takahashi T.let-7 regulates Dicer expression and constitutes a negative feedback loop. Carcinogenesis, 29, 2073-2077 (2008)
  27. Yatabe Y, Takahashi T, Mitsudomi T. Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer. Cancer Res, 68, 2106-2111 (2008)
  28. Yamada H, Yanagisawa K, Tokumaru S, Taguchi A, Nimura Y, Osada H, Nagino M, Takahashi T. Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at 21q11-21 in human lung cancer. Genes Chromosomes Cancer, 47, 810-818 (2008)
  29. Yanagisawa K et al. A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer. J. Natl. Cancer Inst. 99: 858-867 (2007)
  30. Tanaka H et al. Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res. 67: 6007-6011 (2007)
  31. Ebi H et al. Novel NBS1 heterozygous germline mutation causing MRE11-binding domain loss predisposes to common types of cancer. Cancer Res. 67: 11158-1165 (2007)
  32. Takeuchi T et al. Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. J. Clin. Oncol. 24: 1679-1688 (2006)
  33. Hayashita Y et al. A polycistronic miRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 65: 9628-9632 (2005)
  34. Takamizawa J et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 64: 3753-3756 (2004)
  35. He Y et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J. Natl. Cancer Inst. 94: 819-825 (2002)
  36. Kozaki K et al. Establishment and characterization of a human lung cancer cell line NCI-H460-LNM35 with consistent lymphogenous metastasis via both subcutaneous and orthotopic propagation. Cancer Res. 60: 2535-2540 (2000)
  37. Hida T et al. Increased expression of cyclooxygenase 2 frequently occurs in human lung cancers, specifically in adenocarcinomas. Cancer Res. 58: 3761-3764 (1998)
  38. Mitsudomi T et al. Clinical implications of p53 autoantibodies in the sera of patients with non-small-cell lung cancer. J. Natl. Cancer Inst. 90: 1563-1568 (1998)
  39. Masuda A et al. Establishment of human peripheral lung epithelial cell lines (HPL1) retaining differentiated characteristics and responsiveness to EGF, HGF and TGF-b. Cancer Res. 57: 4898-4904 (1997)
  40. Nishio M et al. Prognostic significance of abnormal p53 accumulation in primary, resected non-small cell lung cancers. J. Clin. Oncol. 14: 497-502 (1996)
  41. Suzuki H et al. Altered imprinting in lung cancer. Nature Genet. 6: 332-333 (1994)
  42. Suzuki H et al. p53 mutations in non-small cell lung cancer in Japan: Association between mutations and smoking. Cancer Res. 52: 734-736 (1992)
  43. Takahashi T et al. Identification of intronic point mutations as an alternative mechanism for p53 inactivation in lung cancer. J. Clin. Invest. 86: 363-369 (1990)
  44. Takahashi T et al. p53: a frequent target for genetic abnormalities in lung cancer. Science 246: 491-494 (1989)

Award

1993.10 Incitement Award of the Japanese Cancer Association

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