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Department of Cancer Cell Research

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Chief (Principal Investigator) Hideki Yamaguchi, Ph.D. Researchmap/Google Scholar
e-mail: h-yamaguchi
Research Scientist Yoshiko Nagano, Ph.D. Researchmap/Google Scholar
e-mail: y-nagano
Research Scientist Makoto Miyazaki, Ph.D. Researchmap/Google Scholar
e-mail: m-miyazaki
Research Assistant Yuko Nagamura e-mail: nagamura
Collabolator

*Please add @po.kyoundo.jp after e-mail address

Overview

Cancer has been the leading cause of death in Japan. Metastasis, the spread of cancer to other parts of the body, accounts for about 90% of cancer deaths. Therefore, the control of metastasis is one of the most important issues in the treatment of cancer. However, as the molecular mechanisms regulating metastasis remain incompletely understood, further biological analyses are necessary for deeper understanding to develop anti-metastasis therapy. We aim to understand the role of cellular structures called invadopodia that play important roles in cancer metastasis. We also intend to reveal the mechanisms underlying peritoneal metastasis of scirrhous gastric carcinoma, an aggressive and refractory subtype of gastric carcinoma whose incidence is high in Japan. Our research should provide important insights into the molecular basis of cancer metastasis and lead to the development of novel cancer therapeutics targeting metastasis.

Projects

1. Molecular mechanisms of invadopodia formation and their roles in blood-borne metastasis

Invadopodia are membrane protrusions formed by invasive cancer cells. Invadopodia are rich in actin filaments and matrix metalloproteases with the ability to degrade extracellular matrix (Figs. 1A and B). So far, we have identified several structural and regulatory components of invadopodia and elucidated their functions in invadopodia formation. Moreover, our approach demonstrated that invadopodia play a pivotal role in invasion and hematogenous metastasis of breast cancer (Fig. 1C). We have recently identified several novel components of invadopodia and undertaken their detailed characterization to clarify the molecular mechanisms of invadopodia formation. We are also seeking novel functional molecules and inhibitory compounds by high-throughput screening of gene and chemical libraries, respectively, using invadopodia formation as a readout.
Fig. 1: Invadopodia formation by a breast cancer cell and their role in metastasis. A) A scheme of invadopodia. B) Fluorescent micrographs showing invadopodia formed by a human breast cancer cell. Actin-rich invadopodia were formed at the ventral surface of the cell and the degradation sites of fluorescent gelatin were observed (arrowheads). C) The role of invadopodia in cancer invasion and metastasis. In hematogenous metastasis, invadopodia degrade extracellular matrix within the basement membrane and the blood vessel wall, thereby promoting cancer cell invasion and extravasation. Reproduced with permission from Yamaguchi et al., Oncotarget (2010), and Yamaguchi et al., Eur J Cell Biol (2012).

2. Molecular mechanisms of peritoneal dissemination of scirrhous gastric carcinoma

Scirrhous gastric carcinoma is a refractory carcinoma with poor prognosis owing to its difficulty in early detection, rapid infiltrative growth, and frequent peritoneal dissemination. We are investigating molecular mechanisms governing the aggressive phenotypes of scirrhous gastric carcinoma. We identified several signaling pathways and molecules specifically activated in scirrhous gastric carcinoma. Their roles in peritoneal dissemination and potentials as therapeutic targets are under investigation. Since scirrhous gastric carcinoma is associated with massive fibrosis, we also assess the involvement of tumor microenvironment, including interaction between carcinoma cells and stromal fibroblasts (Fig. 2). Moreover, we make an attempt to visualize tumor clonality and heterogeneity of peritoneally disseminated tumors by multi-color fluorescent imaging (Fig. 3). Our work will contribute to elucidation of the molecular mechanisms underlying progression of scirrhous gastric carcinoma and lead to the development of innovative cancer therapeutics.
Fig. 2: Interaction between scirrhous gastric carcinoma cells and stromal fibroblasts.
Fig. 3: Multi-color fluorescent imaging analysis of peritoneally disseminated tumors of scirrhous gastric carcinoma.

Publications

Last 5 years

  1. Nagamura Y, Miyazaki M, Nagano Y, Yuki M, Fukami K, Yanagihara K, Sasaki K, Sakai R, and Yamaguchi H: PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification. Oncogenesis 10: 25, 2021.
  2. Nakano Y, Takadera M, Miyazaki M, Qiao Z, Nakajima K, Noguchi R, Oyama R, Kimura Y, Okuhiro Y, Yamasaki K, Kunihiro N, Fukushima H, Inoue T, Hara J, Ozawa T, Kondo T, and Ichimura K: Drug screening with a novel tumor-derived cell line identified alternative therapeutic options for patients with atypical teratoid/rhabdoid tumor. Human Cell 34: 271-278, 2021
  3. Kobayashi T, Miyazaki M, Sasaki N, Yamamuro S, Uchida E, Kawauchi D, Takahashi M, Otsuka Y, Kumagai K, Takeuchi S, Toyooka T, Otani N, Wada K, Narita Y, Yamaguchi H, Muragaki Y, Kawamata T, Mori K, Ichimura K and Tomiyama A: Enhanced malignant phenotypes of glioblastoma cells surviving NPe6-mediated photodynamic therapy are regulated via ERK1/2 activation. Cancers 12: 3641, 2020
  4. Yoneda A, Kanemaru K, Matsubara A, Takai E, Shimozawa M, Yanagihara K, Satow R, Yamaguchi H, Nakamura Y, and Fukami K: Phosphatidylinositol 4,5-bisphosphate is localized in the outer leaflet of the plasma membrane and regulates cell adhesion and motility. Biochem. Biophys. Res. Comm. 527: 1050-1056, 2020.
  5. Miyagawa T, Hasegawa K, Aoki Y, Watanabe T, Otagiri Y, Arasaki K, Wakana Y, Asano K, Tanaka M, Yamaguchi H, Tagaya M, and Inoue H: MT1-MMP recruits the ER-Golgi SNARE Bet1 for efficient MT1-MMP transport to the plasma membrane. Journal of Cell Biology 218: 3355-3371, 2019.
  6. Miyamoto S, Narita T, Komiya M, Fujii G, Hamoya T, Nakanishi R, Tamura S, Kurokawa T, Takahashi M, and Mutoh M: Novel screening system revealed that intracellular cholesterol trafficking can be a good target for colon cancer prevention. Scientific Reports 9: 6192, 2019.
  7. Kannagi M, Hasegawa A, Nagano Y, Kimpara S, Suehiro Y: Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL. Retrovirology 16: 23, 2019.
  8. Kannagi M, Hasegawa A, Nagano Y, Iino T, Okamura J, Suehiro Y: Maintenance of long remission in adult T-cell leukemia by Tax-targeted vaccine: A hope for disease-preventive therapy. Cancer Sci. 110: 849-857, 2019.
  9. Miyazaki M, Otomo R, Matsushima-Hibiya Y, Suzuki H, Nakajima A, Abe N, Tomiyama A, Ichimura K, Matsuda K, Watanabe T, Ochiya T, Nakagama H, Sakai R, and Enari M: The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas. Cell Death Discov. 4: 56, 2018.
  10. Yamaguchi S, Fujii T, Izumi Y, Fukumura Y, Han M, Yamaguchi H, Akita T, Yamashita C, Kato S, and Sekiya T: Identification and characterization of a novel adenomatous polyposis coli mutation in adult pancreatoblastoma. Oncotarget 9: 10818-10827, 2018.
  11. Miyamoto S, Nagamura Y, Nakabo A, Okabe A, Yanagihara K, Fukami K, Sakai R, and Yamaguchi H: Aberrant alternative splicing of RHOA is associated with loss of its expression and activity in diffuse-type gastric carcinoma cells. Biochem. Biophys. Res. Comm. 495: 1942-1947, 2018.
  12. Yamamoto Y, Tomiyama A, Sasaki N, Yamaguchi H, Shirakihara T, Nakashima K, Kumagai K, Takeuchi S, Toyooka T, Otani N, Wada K, Narita Y, Ichimura K, Sakai R, Namba H, and Mori K: Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft. Biochem. Biophys. Res. Comm. 495: 1292-1299, 2018.
  13. Yamaguchi H, Ito Y, Miura N, Nagamura YNakabo A, Fukami K, Honda K, and Sakai R: Actinin-1 and actinin-4 play essential but distinct roles in invadopodia formation by carcinoma cells. Eur. J. Cell Biol. 96: 685-694, 2017.
  14. Nakashima K, Uekita T, Yano S, Kikuchi J, Nakanishi R, Sakamoto N, Fukumoto K, Nomoto A, Kawamoto K, Shibahara T, Yamaguchi H, and Sakai R: Novel small molecule inhibiting CDCP1-PKCδ pathway reduces tumor metastasis and proliferation. Cancer Sci. 108: 1049-1057, 2017.
  15. Terasaki M, Maeda H, Miyashita K, Tanaka T, Miyamoto S, Mutoh M: A marine bio-functional lipid, fucoxanthinol, attenuates human colorectal cancer stem-like cell tumorigenicity and sphere formation. J. Clin. Biochem. Nutr. 61: 25-32, 2017.
  16. Onuma W, Asai D, Tomono S, Miyamoto S, Fujii G, Hamoya T, Nagano A, Takahashi S, Masumori S, Miyoshi N, Wakabayashi K, Mutoh M: Anticarcinogenic Effects of Dried Citrus Peel in Colon Carcinogenesis Due to Inhibition of Oxidative Stress. Nutr. Cancer. 69: 855-861, 2017.
  17. Hamoya T, Miyamoto S, Tomono S, Fujii G, Nakanishi R, Komiya M, Tamura S, Fujimoto K, Toshima J, Wakabayashi K, Mutoh M: Chemopreventive effects of a low-side-effect antibiotic drug, erythromycin, on mouse intestinal tumors. J. Clin. Biochem. Nutr. 60: 199-207, 2017.
  18. Miyamoto S, Komiya M, Fujii G, Hamoya T, Nakanishi R, Fujimoto K, Tamura S, Kurokawa Y, Takahashi M, Ijichi T, Mutoh M: Preventive Effects of Heat- Killed Enterococcus faecalis Strain EC-12 on Mouse Intestinal Tumor Development. Int. J. Mol. Sci.18: 826, 2017.
  19. Noma N, Fujii G, Miyamoto S, Komiya M, Nakanishi R, Shimura M, Tanuma SI, Mutoh M: Impact of Acetazolamide, a Carbonic Anhydrase Inhibitor, on the Development of Intestinal Polyps in Min Mice. Int. J. Mol. Sci.18: E851, 2017.

Before 2016 (selected)

  1. Tomiyama A, Uekita T, Kamata R, Sasaki K, Takita J, Ohira M, Nakagawara A, Kitanaka C, Mori K, Yamaguchi H, and Sakai R: Flotillin-1 regulates oncogenic signaling in neuroblastoma through receptor endocytosis of anaplastic lymphoma kinase. Cancer Res. 74: 3790-3801, 2014.
  2. Otsubo C, Otomo R, Miyazaki M, Matsushima-Hibiya Y, Kohno T, Iwakawa R, Takeshita F, Okayama H, Ichikawa H, Saya H, Kiyono T, Ochiya T, Tashiro F, Nakagama H, Yokota J, Enari M: TSPAN2 Is Involved in Cell Invasion and Motility during Lung Cancer Progression. Cell Rep. 7: 527-538, 2014.
  3. Otomo R, Otsubo C, Matsushima-Hibiya Y, Miyazaki M, Tashiro F, Ichikawa H, Kohno T, Yokota J, Nakagama H, Taya Y, Enari M: TSPAN12 is a critical factor for cancer-fibroblast cell contact-mediated cancer invasion. Proc. Natl. Acad. Sci. USA 111: 18691-18696, 2014.
  4. Sato M, Kadota M, Tang B, Yang HH, Yang YA, Shan M, Weng J, Welsh MA, Flanders KC, Nagano Y, Michalowski AM, Clifford RJ, Lee MP, Wakefield LM: An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-beta in human breast cancer. Breast Cancer Res. 16: R57, 2014.
  5. Ohata H, Miyazaki M, Otomo R, Matsushima-Hibiya Y, Otsubo C, Nagase T, Arakawa H, Yokota J, Nakagama H, Taya Y, Enari M: NuMA Is Required for the Selective Induction of p53 Target Genes. Mol. Cell. Biol. 33: 2447-2457, 2013.
  6. Kanemaru K*, Nakamura Y*, Sato K, Takahashi S, Yamaguchi M, Ichinohe M, Kiyonari H, Shioi G, Asagiri M, Jamora C, Kouchi Z, Yamaguchi H, and Fukami K: Epidermal loss of phospholipase C δ1 results in myeloproliferation in mice. Nature Commun. 3: 963, 2012.
  7. Kohn EA, Yang YA, Du Z, Nagano Y, Van Schyndle CM, Herrmann MA, Heldman M, Chen JQ, Stuelten CH, Flanders KC, Wakefield LM: Biological responses to TGF-beta in the mammary epithelium show a complex dependency on Smad3 gene dosage with important implications for tumor progression. Mol. Cancer Res. 10: 1389-1399, 2012.
  8. Yamaguchi H, Yoshida S, Muroi E, Yoshida N, Kawamura M, Kouchi Z, Nakamura Y, Sakai R, and Fukami K: PI3-kinase signaling pathway mediated by p110α regulates invadopodia formation. J. Cell Biol. 193: 1275-1288, 2011.
  9. Koinuma D, Shinozaki M, Nagano Y, Ikushima H, Horiguchi K, Goto K, Chano T, Saitoh M, Imamura T, Miyazono K, Miyazawa K: RB1CC1 protein positively regulates transforming growth factor-beta signaling through the modulation of Arkadia E3 ubiquitin ligase activity. J. Biol. Chem. 286: 32502-32512, 2011.
  10. Nagano Y, Koinuma D, Miyazawa K, Miyazono K: Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells. J. Biochem. 147: 545-554, 2010.
  11. Yamaguchi H, Takeo Y, Yoshida S, Kouchi Z, Nakamura Y, and Fukami K: Lipid rafts and caveolin-1 are required for invadopodia formation and extracellular matrix degradation by human breast cancer cells. Cancer Res. 69: 8594-8602, 2009.
  12. Oser M, Yamaguchi H, Mader CC, Arias M, DesMarais V, van Rheenen J, Koleske AJ, and Condeelis J: Cortactin regulates cofilin and N-WASP activities to control the stages of invadopodium assembly and maturation. J. Cell Biol. 186: 571-587, 2009.
  13. Philippar U, Roussos ET, Oser M, Yamaguchi H, Kim HD, Giampieri S, Wang Y, Goswami S, Wyckoff JB, Lauffenburger DA, Sahai E, Condeelis JS, and Gertler FB: A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev. Cell 15: 813-828, 2008.
  14. Nagano Y, Mavrakis KJ, Lee KL, Fujii T, Koinuma D, Sase H, Yuki K, Isogaya K, Saitoh M, Imamura T, Episkopou V, Miyazono K, Miyazawa K: Arkadia induces degradation of SnoN and c-Ski to enhance transforming growth factor-beta signaling. J. Biol. Chem. 282: 20492-20501, 2007.
  15. Yamaguchi H, Lorenz M, Kempiak S, Sarmiento C, Coniglio S, Symons M, Segall J, Eddy R, Miki H, Takenawa T, and Condeelis J: Molecular mechanisms of invadopodium formation: The role of the N-WASP-Arp2/3 complex pathway and cofilin. J. Cell Biol. 168: 441-452, 2005.
  16. Oikawa T, Yamaguchi H, Itoh T, Kato M, Ijuin T, Yamazaki D, Suetsugu S, and Takenawa T: PtIns(3,4,5)P3 binding is necessary for WAVE2-induced formation of lamellipodia. Nature Cell Biol. 6: 420-426, 2004.
  17. Lorenz M, Yamaguchi H, Wang Y, Singer RH, and Condeelis JS: Imaging sites of N-WASP activity in lamellipodia and invadopodia of carcinoma cells. Curr. Biol. 14: 697-703, 2004.
  18. Yamaguchi H, Miki H, and Takenawa T: Neural Wiskott-Aldrich syndrome protein is involved in hepatocyte growth factor-induced migration, invasion, and tubulogenesis of epithelial cells. Cancer Res. 62: 2503-2509, 2002.
  19. Martinez-Quiles N, Rohatgi R, Anton IM, Medina M, Saville SP, Miki H, Yamaguchi H, Takenawa T, Hartwig JH, Geha RS, and Ramesh N: WIP regulates N-WASP-mediated actin polymerization and filopodium formation. Nature Cell Biol. 3: 484-491, 2001.
  20. Miki H, Yamaguchi H, Suetsugu S, and Takenawa T: IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 408: 732-735, 2000.
  21. Yamaguchi H, Miki H, Suetsugu S, Ma L, Kirschner MW, and Takenawa T: Two tandem verprolin homology domains are necessary for a strong activation of Arp2/3 complex-induced actin polymerization and induction of microspike formation by N-WASP. Proc. Natl. Acad. Sci. USA 97: 12631-12636, 2000.