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. 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 Masako Yuki

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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.


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.

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. 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)
  2. 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)
  3. 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)
  4. 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)
  5. 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)
  6. 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)
  7. Yamaguchi H, Ito Y, Miura N, Nagamura Y, Nakabo 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)
  8. 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)
  9. Terasaki M, Maeda H, Miyashita K, Tanaka T, Miyamoto S, and 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)
  10. Onuma W, Asai D, Tomono S, Miyamoto S, Fujii G, Hamoya T, Nagano A, Takahashi S, Masumori S, Miyoshi N, Wakabayashi K, and Mutoh M: Anticarcinogenic Effects of Dried Citrus Peel in Colon Carcinogenesis Due to Inhibition of Oxidative Stress. Nutr. Cancer. 69: 855-861 (2017)
  11. Hamoya T, Miyamoto S, Tomono S, Fujii G, Nakanishi R, Komiya M, Tamura S, Fujimoto K, Toshima J, Wakabayashi K, and Mutoh M: Chemopreventive effects of a low-side-effect antibiotic drug, erythromycin, on mouse intestinal tumors. J. Clin. Biochem. Nutr. 60: 199-207 (2017)
  12. Miyamoto S, Komiya M, Fujii G, Hamoya T, Nakanishi R, Fujimoto K, Tamura S, Kurokawa Y, Takahashi M, Ijichi T, and Mutoh M: Preventive Effects of Heat- Killed Enterococcus faecalis Strain EC-12 on Mouse Intestinal Tumor Development. Int. J. Mol. Sci. 18: 826 (2017)
  13. Noma N, Fujii G, Miyamoto S, Komiya M, Nakanishi R, Shimura M, Tanuma SI, and 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)
  14. Nakanishi M, Chen Y, Qendro V, Miyamoto S, Weinstock E, Weinstock GM, and Rosenberg DW: Effects of walnut consumption on colon carcinogenesis and microbial community structure. Cancer Prev. Res. 9: 692-703 (2016)
  15. Onuma W, Tomono S, Miyamoto S, Fujii G, Hamoya T, Fujimoto K, Miyoshi N, Sasazuki S, Fukai F, Wakabayashi K, and Mutoh M: Irsogladine maleate, a gastric mucosal protectant, suppresses intestinal polyp development in Apc-mutant mice. Oncotarget. 7: 8640-8652 (2016)
  16. Miyamoto S, Terasaki M, Ishigamori R, Fujii G, and Mutoh M: Prospective Targets for Colon Cancer Prevention: from Basic Research, Epidemiology and Clinical Trial. Journal of Digestive Cancer Reports. 42(2): 64-76 (2016)
  17. Mutoh M, Fujii G, and Miyamoto S: Where the colorectal cancer chemoprevention is and where it is going. Nihon Shokakibyo Gakkai Zasshi 113: 1186-1190 (2016)
  18. Hamoya T, Fujii G, Miyamoto S, Takahashi M, Totsuka Y, Wakabayashi K, Toshima J, and Mutoh M: Effects of NSAIDs on the risk factors of colorectal cancer: a mini review. Genes and Environment 38: 6 (2016)
  19. Miyamoto S, Fujii G, Komiya M, Terasaki M, and Mutoh M: Potential for Sesame Seed-Derived Factors to Prevent Colorectal Cancer. In: Ullah MF and Ahmad A (Eds.), Critical Dietary Factors in Cancer Chemoprevention, Springer, 183-197 (2016)
  20. Ueno H, Tomiyama A, Yamaguchi H, Uekita T, Shirakihara T, Nakashima K, Otani N, Wada K, Sakai R, Arai H, and Mori K: Augmentation of invadopodia formation in temozolomide-resistant or adopted glioma is regulated by c-Jun terminal kinase-paxillin axis. Biochem. Biophys. Res. Comm. 468: 240-247 (2015)
  21. Komiya M, Fujii G, Miyamoto S, Takahashi M, Ishigamori R, Onuma W, Ishino K, Totsuka Y, Fujimoto K, and Mutoh M: Suppressive effects of the NADPH oxidase inhibitor apocynin on intestinal tumorigenesis in obese KK-Ay and Apc mutant Min mice. Cancer Sci. 106: 1499-1505 (2015)
  22. Shimizu S, Miyamoto S, Fujii G, Nakanishi R, Onuma W, Ozaki Y, Fujimoto K, Yano T, and Mutoh M: Suppression of intestinal carcinogenesis in Apc-mutant mice by limonin. J. Clin. Biochem. Nutr. 57: 39-43 (2015)
  23. Yamaguchi H, and Sakai R: Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancers 7: 2054-2062 (2015)
  24. Mutoh M, Fujii G, Miyamoto S, Nakanishi R, Miura A, and Sasazuki S: Colorectal cancer prevention by the way of drug repositioning. Ulcer Res. 42: 5-11 (2015)
  25. 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)
  26. Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, and Sakai R: Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and FGFR inhibitors. Cancer Sci. 105: 528-536 (2014)
  27. Otomo R, Otsubo C, Matsushima-Hibiya Y, Miyazaki M, Tashiro F, Ichikawa H, Kohno T, Yokota J, Nakagama H, Taya Y, and Enari M: TSPAN12 is a critical factor for cancer-fibroblast cell contact-mediated cancer invasion. Proc. Natl. Acad. Sci. USA 111:18691-18696 (2014)
  28. 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, and Enari M: TSPAN2 Is Involved in Cell Invasion and Motility during Lung Cancer Progression. Cell Rep. 7:527-538 (2014)
  29. Yamaguchi H, Yoshida N, Takanashi M, Ito Y, Fukami K, Yanagihara K, Yashiro M, and Sakai R: Stromal fibroblasts mediate extracellular matrix remodeling and invasion of scirrhous gastric carcinoma cells. PLOS ONE 9: e85485 (2014)