Journal
JOURNAL OF CELL SCIENCE
Volume 125, Issue 4, Pages 858-868Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.089995
Keywords
Glioblastoma; Invasion; Rho-family GTPase; FRET; Zizimin1 (DOCK9)
Categories
Funding
- Sagawa Cancer Research Grant
- Ministry of Education, Culture, Sports and Science (MEXT), Japan
- Global Center of Excellence Center for Frontier Medicine
- Cancer Research UK [15154] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [21689039, 11J06044, 21659339] Funding Source: KAKEN
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Two-photon excitation microscopy was used to visualized two different modes of invasion at perivascular and intraparenchymal regions of rat C6 glioblastoma cells that were orthotopically implanted into rat brains. Probes based on the principle of Forster resonance energy transfer (FRET) further revealed that glioblastoma cells penetrating the brain parenchyma showed higher Rac1 and Cdc42 activities and lower RhoA activity than those advancing in the perivascular regions. This spatial regulation of Rho-family GTPase activities was recapitulated in three-dimensional spheroid invasion assays with rat and human glioblastoma cells, in which multipod glioblastoma cells that invaded the gels and led the other glioblastoma cells exhibited higher Rac1 and Cdc42 activities than the trailing glioblastoma cells. We also studied the Cdc42-specific guanine nucleotide exchange factor Zizimin1 (also known as DOCK9) as a possible contributor to this spatially controlled activation of Rho-family GTPases, because it is known to play an essential role in the extension of neurites. We found that shRNA-mediated knockdown of Zizimin1 inhibited formation of pseudopodia and concomitant invasion of glioblastoma cells both under a 3D culture condition and in vivo. Our results suggest that the difference in the activity balance of Rac1 and Cdc42 versus RhoA determines the mode of glioblastoma invasion and that Zizimin1 contributes to the invasiveness of glioblastoma cells with high Rac1 and Cdc42 activities.
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