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Review
. 2021 Apr 14;13(8):1882.
doi: 10.3390/cancers13081882.

Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis

Arpita Datta  1 , Shuo Deng  1 , Vennila Gopal  1 , Kenneth Chun-Hong Yap  1   2 , Clarissa Esmeralda Halim  1 , Mun Leng Lye  1 , Mei Shan Ong  1 , Tuan Zea Tan  3 , Gautam Sethi  2   4 , Shing Chuan Hooi  1   4 , Alan Prem Kumar  2   3   4   5 , Celestial T Yap  1   4   5
Affiliations
Review

Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis

Arpita Datta et al. Cancers (Basel). .

Abstract

In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells-highlight some future perspectives in cancer therapy by targeting cytoskeleton.

Keywords: actin cytoskeleton; epithelial to mesenchymal transition; metastasis; multidrug resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
EMT-MET model for the metastatic cascade: Epithelial cancer cells undergo EMT, which causes them to lose their cell-cell junctions and gain the ability to invade the surrounding tissue parenchyma (Step 1). These EMT-induced cells may then intravasate into the systemic circulation (Step 2) and must survive in the circulation (Step 3) before reaching the target organ site. Upon reaching the target organ site, the cells must then extravasate into the tissue parenchyma (Step 4), following which they may either enter a state of dormancy or form micro metastases. Subsequent development into clinically detectable and potentially life-threatening macro metastases requires MET activation (Step 5).
Figure 2
Figure 2
Layout of an epithelial-mesenchymal transition (EMT) transition process and forward migration of cells. Epithelial cells are bound together by tight junctions, adherens junctions, and desmosomes. The adherens junctions are cadherin-based and actin filament-associated cell-to-cell junctions that are composed of defined protein complexes. Epithelial cells are tightly secured to the basement membrane via highly specialized integrin-mediated attachment structures. Signaling pathways are said to trigger the EMT process—propagated by various EMT-TFs, such as ZEB, SNAIL, and TWIST that curb gene expression (listed in the blue box) related with the epithelial state and induce expression of genes associated with the mesenchymal state (listed in the pink box). Mesenchymal cells contain vimentin-based intermediate filaments and use integrin-containing focal adhesions to attach to the ECM. In contrast to epithelial cells, mesenchymal cell migration presents a leading and trailing edge and an extensively reorganized cytoskeleton. Lamellipodia is formed by polymerization of actin by the WAVE-Arp2/3 nucleation mechanism.
Figure 3
Figure 3
A schematic diagram illustrating the resistance mechanisms associated with anti-microtubule drugs. These drugs cross the lipid bilayer of the cell membrane and then bind themselves to β-tubulin to alter the microtubule dynamics, causing mitotic arrest and consequent apoptosis. Drugs can be effluxed before reaching the cellular target with the aid of functional drug transport protein. Disruption in the tubulin/microtubule system can avert anti-microtubule drugs from disrupting the microtubules and leading to drug resistance. Before drug binding occurs, signaling and anti-apoptotic factors may also contribute to drug resistance. MF: microfilaments, Mt: microtubules. [212]. The figure was created with BioRender.com (Accessed on 1 February 2021) and was exported under a paid subscription.
Figure 4
Figure 4
A diagram illustrating the mechanism of action of Antibody-Drug Conjugate (ADC) in a cancer cell. (A): High-affinity Antibody binds to the drug, forming ADC, entering the double lipid-membrane layer of the cell to cause cell death. (B): ADC binds to the pro-survival receptor of cancer cells, inhibiting its function, commencing apoptosis. (C): ADC binds to both the membrane-surface antigen of the cancer cell and an effector cell in the immune system, inducing cellular cytotoxicity lysing the cancer cells. The figure was created with BioRender.com (Accessed on 1 February 2021) and was exported under a paid subscription.
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