Glioblastoma motility occurs in the absence of actin polymer

Panopoulos, Andreas; Howell, Michael; Fotedar, Rati; Margolis, Robert L.

doi:10.1091/mbc.e10-10-0849

Cited by 40 publications

(40 citation statements)

References 40 publications

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“…The gradient of Rho-family GTPase activity within the glioblastoma tissue strongly supports the idea that the two glioblastoma invasion modes are correlated with the activities of Rho-family GTPases. Interestingly, recent studies by Panopoulos et al showed that mesenchymal migration of glioblastoma cells does not require Rac1 activity on 2D substrates (Panopoulos et al, 2011). This observation suggests that glioblastoma cells do not require Rac1 activity to move without marked resistance on dishes or around blood vessels.…”

Section: Discussionmentioning

confidence: 99%

In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion

Hirata

Yukinaga

Kamioka

et al. 2012

Journal of Cell Science

122

110

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SummaryTwo-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 Förster 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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Section: Discussionmentioning

confidence: 99%

In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion

Hirata

Yukinaga

Kamioka

et al. 2012

Journal of Cell Science

122

110

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“…Restructuring of the cytoskeleton is imperative in the process of cell proliferation and in migration and invasion of cancer cells. In glioblastoma, control of cytoskeletal dynamics has been attributed to the orchestrated activity of several signaling pathways, including Rac1, RhoA, and RhoC (45)(46)(47). Interestingly, the two latter pathways have also been implicated in c-Jun regulation (48,49).…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation

Blau

Knirsh

Ben-Dror

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Although the protooncogene c-Jun plays a critical role in cell proliferation, cell death, and malignant transformation, DNA microarray screens have identified only a few human cancer types with aberrant expression of c-Jun. Here, we show that c-Jun accumulation is robustly elevated in human glioblastoma and that this increase contributes to the malignant properties of the cells. Most importantly, the increase in c-Jun protein accumulation occurs with no corresponding increase in c-Jun mRNA or the half-life of the c-Jun protein but, rather, in the translatability of the transcript. The c-Jun 5′UTR harbors a potent internal ribosomal entry site (IRES) with a virus-like IRES domain that directs cap-independent translation in glioblastoma cells. Accumulation of c-Jun is not dependent on MAPK activity but can be stimulated by a cytoskeleton-dependent pathway. Our findings provide evidence that human c-Jun is an IRES-containing cellular transcript that contributes to cancer development through translational activation. This previously undescribed mechanism of c-Jun regulation might also be relevant to other types of human cancer and offers unique potential targets for therapy.

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“…Although the molecular mechanisms underlying these effects are not entirely clear, the integrity of the microtubule network is a well-established player in controlling the balance of Rho GTPase activities and, therefore, F-actin assembly and actomyosin contractility in 2D cultures (Etienne-Manneville, 2013). Interestingly, specific cell types, such as glioblastoma cells have been reported to be actin independent but require microtubules for migration in 2D (Panopoulos et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Microtubules in 3D cell motility

Bouchet

Akhmanova

2017

Journal of Cell Science

104

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Three-dimensional (3D) cell motility underlies essential processes, such as embryonic development, tissue repair and immune surveillance, and is involved in cancer progression. Although the cytoskeleton is a well-studied regulator of cell migration, most of what we know about its functions originates from studies conducted in twodimensional (2D) cultures. This research established that the microtubule network mediates polarized trafficking and signaling that are crucial for cell shape and movement in 2D. In parallel, developments in light microscopy and 3D cell culture systems progressively allowed to investigate cytoskeletal functions in more physiologically relevant settings. Interestingly, several studies have demonstrated that microtubule involvement in cell morphogenesis and motility can differ in 2D and 3D environments. In this Commentary, we discuss these differences and their relevance for the understanding the role of microtubules in cell migration in vivo. We also provide an overview of microtubule functions that were shown to control cell shape and motility in 3D matrices and discuss how they can be investigated further by using physiologically relevant models.

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Glioblastoma motility occurs in the absence of actin polymer

Cited by 40 publications

References 40 publications

In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion

In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion

Aberrant expression of c-Jun in glioblastoma by internal ribosome entry site (IRES)-mediated translational activation

Microtubules in 3D cell motility

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