HAGA HisashiProfessor

Laboratory of Cell Dynamics
Research Theme
Collective Behavior and 3D Morphogenesis of Epithelial Cells, Cancer Cell Invasion
Research Keywords

collective cell movement, 3D morphogenesis, cancer cell invasion

Overview of Research

■3D morphogenesis of epithelial sheets using viscoelastic substrates
3D morphogenesis is an essential process for various phenomena such as embryonic development and tissue formation. Mechanical properties of the extracellular matrix are understood as factors that affect the cell behavior. We show that a collagen gel overlay induced epithelial sheet folding from the periphery that migrated inwardly, resulting in the formation of a 3D luminal structure in a collagen gel. We also cultured epithelial cells on a viscous substrate. The cells presented a tulip hat-like 3D morphology induced by the deformation of the peripheral substrate.

■Acceleration of metastatic growth of cancer cells induced by substrate stiffness
Recent studies have shown that stiff substrates trigger cancer progression such as metastasis and cell proliferation. For example, it is well known that malignant breast tissues are stiff compared with normal mammary tissues. We found that stiff substrates enhanced cancer progression by upregulating matrix metalloproteinase-7 expression, which is an indicator of poor prognosis, through the positive feedback loop of yes-associated protein, epidermal growth factor receptor, integrin and myosin regulatory light chain in colorectal cancer.



3D morphogenesis of animal and plant organs is the final mystery in biology because the blueprints to form 3D structure are not written in DNA. We try to understand the mechanisms that determine the 3D shape of a biological body from the viewpoint the physical properties of the extracellular environment. Moreover, we try to reveal the mechanisms of malignant alteration induced by failure of the relationship between normal cells and the extracellular environment.

Representative Publications

K. Onishi, S. Ishihara, M. Takahashi, A. Sakai, A. Enomoto, K. Suzuki, and H. Haga: Substrate stiffness induces nuclear localization of myosin regulatory light chain to suppress apoptosis, FEBS Letters, 597, 643-656 (2023).

S. Ishihara, H. Kurosawa, and H. Haga: Stiffness-Modulation of Collagen Gels by Genipin-Crosslinking for Cell Culture, Gels, 9, 148 (2023).

S. Ishida-Ishihara, R. Takada, K. Furusawa, S. Ishihara, and H. Haga: Improvement of the cell viability of hepatocytes cultured in three-dimensional collagen gels using pump-free perfusion driven by water level difference, Scientific Reports, 12, 20269, 1-11 (2022).

Y. Kumagai, J. Nio-Kobayashi, S. Ishihara, A. Enomoto, M. Akiyama, R. Ichihara, and H. Haga: The Interferon-β/STAT1 Axis Drives the Collective Invasion of Skin Squamous Cell Carcinoma with Sealed Intercellular Spaces, Oncogenesis, 11, 27 (2022).

H. Oyama, A. Nukuda, S. Ishihara, and H. Haga: Soft Surfaces Promote Astrocytic Differentiation of Mouse Embryonic Neural Stem Cells via Dephosphorylation of MRLC in the Absence of Serum, Scientific Reports, 11, 19574, 1-11 (2021).

S. Ishida-Ishihara, M. Akiyama, K. Furusawa, I. Naguro, H. Ryuno, T. Sushida, S. Ishihara, and H. Haga: Osmotic Gradients Induce Stable Dome Morphogenesis on Extracellular Matrix, Journal of Cell Science, 133, jcs243865 (2020).

Y. Kumagai, J. Nio-Kobayashi, S. Ishida-Ishihara, H. Tachibana, R. Omori, A. Enomoto, S. Ishihara, and H. Haga: The intercellular expression of type-XVII collagen, laminin-332, and integrin-β1 promote contact following during the collective invasion of a cancer cell population, Biochem. Biophys. Res. Commun., 514, 1115-1121 (2019).



<Office Hour>
– Time: Anytime during the lecture period
– Place: Science Bldg. No.2, 6F, #2-612
Please contact in advance by E-mail.
E-mail: haga[at]