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Review
. 2025 Mar;82(3):91-97.
doi: 10.1002/cm.21880. Epub 2024 May 18.

Nucleating amoeboid cancer cell motility with Diaphanous related formins

Neelakshi Kar  1 , Jeremy S Logue  1
Affiliations
Review

Nucleating amoeboid cancer cell motility with Diaphanous related formins

Neelakshi Kar et al. Cytoskeleton (Hoboken). 2025 Mar.

Abstract

The tissue invasive capacity of cancer cells is determined by their phenotypic plasticity. For instance, mesenchymal to amoeboid transition has been found to facilitate the passage of cancer cells through confined environments. This phenotypic transition is also heavily regulated by the architecture of the actin cytoskeleton, which may increase myosin contractility and the intracellular pressure that is known to drive bleb formation. In this review, we highlight several Diaphanous related formins (DRFs) that have been found to promote or suppress bleb formation in cancer cells, which is a hallmark of amoeboid migration. Based on the work discussed here, the role of the DRFs in cancer(s) is worthy of further scrutiny in animal models, as they may prove to be therapeutic targets.

Keywords: Diaphanous related formin; actin; amoeboid; bleb; cancer.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Drivers of mesenchymal versus amoeboid migration in cancer cells. Amoeboid migration is driven by myosin and actin bundling proteins, whereas integrin adhesion and Arp2/3 drive mesenchymal migration. A formin may drive mesenchymal or amoeboid migration. Protrusion of the leading edge is driven by F‐actin in mesenchymal cells, whereas protrusion of the leading edge is driven by intracellular pressure (i.e., blebs) in amoeboid cells. Created with BioRender.com
FIGURE 2
FIGURE 2
Diaphanous related formins. Upon binding a Rho GTPase, release from autoinhibition induces Diaphanous related formin (DRF) dimerization and barbed‐end binding. Actin polymerization is accelerated by the recruitment of profilin bound G‐actin by the FH1 domains. GTPase binding domain (GBD), Diaphanous inhibitory domain (DID), dimerization domain (DD), formin homology 1 (FH1), formin homology 2 (FH2), Diaphanous‐autoregulatory domain (DAD). Created with BioRender.com
FIGURE 3
FIGURE 3
Schematic representation of Dia1 and Dia2 regulation by DIP. Briefly, the activation of Dia1 by DIP starts a positive feedback loop (+) that activates RhoA through LARG. In contrast, Dia2 is inhibited by DIP, which is frequently lost (*) in advanced cancers. Specific chemokines have been shown to induce the binding of DIP to Dia2. Created with BioRender.com
FIGURE 4
FIGURE 4
Schematic representation of a Dia2 negative feedback loop. Briefly, the inhibition of Dia2 by DIP starts a negative feedback loop (−) that induces microtubule instability that in turn releases GEF‐H1 to activate RhoA. Dia2 is frequently lost (*) in advanced cancers. Created with BioRender.com
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