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 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. 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 in press
  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. 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)
  8. 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)
  9. 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)
  10. 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)
  11. 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)
  12. 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-PKCĪ“ pathway reduces tumor metastasis and proliferation. Cancer Sci. 108: 1049-1057 (2017)
  13. 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)
  14. 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)
  15. 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)
  16. 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)
  17. 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)