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Tumor Discovery Understanding glioblastoma invasion and therapy

with the perivascular space, occurs but is less common. migration and invasion, whereas Cdc42 depletion reduced
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GBM does not invade across sulcal margins. 72 invasion. Rac1 inhibition suppressed GBM cell invasion. 97
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Both white-matter tracts and blood vessel scaffolds are RhoA’s role in the GBM invasion is less well-defined.
invaded by GBM cells. Signaling pathways underlying RhoA expression decreases with increasing grade of glial
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white-matter tract invasion remain largely unknown, malignancy. RhoA and Rac1 are known to be functionally
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while molecular drivers of perivascular GBM invasion are antagonistic, with Rac1 activation predominating in
well-characterized. Endothelial basement membranes mesenchymal migration and RhoA mediating the
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are enriched with collagen and fibronectin, providing contractility required for so-called amoeboid motility.
99
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valuable substrates for integrin engagement that facilitate Some RhoA activity is required for early adhesion and
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coordinated movement. Blood vessels offer a large supply trailing edge contraction in mesenchymal motility, and
of oxygen/nutrients that support malignant proliferation RhoA regulates the expression of transmembrane matrix
and attract invasive cells. In contrast, the parenchymal metalloproteases (MMPs) that remodel the ECM for
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extracellular matrix (ECM) lacks stiffening molecules such mesenchymal invasion. In vivo, RhoA activation is
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as collagen and fibronectin and is instead composed of predominantly associated with perivascular invasion.
hygroscopic molecules such as proteoglycans, hyaluronans, Importantly, directed invasion in GBM can be triggered
tenascins, and link proteins. These molecules retain in response to ECM composition (stiffness, porosity, and
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water, creating a gelatinous ECM that densely fills the topography), autocrine or paracrine signaling factors
2+
extracellular compartment and leaves a limited amount of (pleiotrophin, CXCL12, glutamate), 102-104 or ion flux (Ca ,
-
+ 105-107
unoccupied extracellular space available to accommodate Cl , K ).
invasive movement. Intraparenchymal invasion requires 7.2.2. Roles for GTPases effector proteins in GBM
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GBM cells to erode their way through the existing tissue invasion: The formins
architecture. Still, GBM extensively invades cerebral
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gray matter, using proteolytic-guided mesenchymal and The formin family of proteins is an evolutionarily conserved
collective invasion strategies. 80-82 group of Rho GTPase effector proteins that make essential
contributions to the organization and maintenance of the
7.2. Molecular drivers of GBM invasion: Rho proteins actin and microtubule cytoskeletal systems. Human cells
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and their effectors express at least 15 different formin family proteins. The
Dynamic remodeling of both the actin and microtubule diaphanous-related formin subfamily, also referred to as
cytoskeletal systems is required for microstructural mammalian diaphanous-related formins (mDias), is the
and macrostructural patterns of GBM invasion. Actin most extensively characterized subgroup of formins and
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polymerization drives leading-edge protrusions, and includes mDia1, mDia2, and mDia3 (Figure 4).
genetic or pharmaceutical targeting of actin nucleator The mDia formins are well known for their roles in
proteins, such as formins or Arp2/3, have been shown to facilitating actin polymerization. The exposed formin
reduce GBM invasion. 84-89 Microtubules are also required homology (FH2) domains of active mDia formins
to support elongating cell protrusions and to transport homodimerize to form a ring structure that stabilizes
ECM-degrading enzymes to leading-edge structures. 90,91 G-actin trimers and catalyzes energetically unfavorable
Microtubule targeting agents also reduce GBM invasion. 91,92 nucleation of actin filaments. mDia formins are among
the few Rho GTPase effector proteins that directly
7.2.1. Rho guanosine triphosphatases (GTPases) in influence both actin and microtubule dynamics. In
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GBM invasion addition to their roles as mediators of actin nucleation,
In GBM, differential activation of molecular switches polymerization, and bundling, mDias directly bind to and
called Rho GTPases coordinates cytoskeletal remodeling stabilize microtubules. 111,112
required for invasive motility and dictates specific Temporal regulation of mDias is controlled by Rho
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invasion programs. Rho GTPases cell division control GTPase activity, which is, in turn, controlled by external
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protein 42 homolog (Cdc42) and Ras-related C3 botulinum signaling cues. Thus, Rho GTPases link mDia activation
toxin substrate 1 (Rac1) are upregulated in gliomas relative with the environmentally directed cellular demand for
to normal brain tissue. Cdc42 and Rac1 activation is cytoskeletal modification. Several different Rho GTPases
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associated with pseudopodial extension into the brain activate mDia1, mDia2, and mDia3, with each isoform
parenchyma and guidance of other tumor cells with lower exhibiting different GTPase specificities that facilitate a
Cdc42 and Rac1 activation toward the invasive front. In widely diverse set of cellular processes and macrostructural
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U87 GBM spheroid invasion, activated Cdc42 increased modifications.

Volume 4 Issue 2 (2025) 27 doi: 10.36922/td.8578