Targeting the WASF3 complex to suppress metastasis
Ameya J Limaye1, Matthew K Whittaker1, George N Bendzunas1
1Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, 240W. Green St, Athens, GA 30602, United States.
Abstract:
Wiskott-Aldrich syndrome protein family members (WASF) regulate the dynamics of the actin cytoskeleton, which plays an instrumental role in cancer metastasis and invasion. WASF1/2/3 forms a hetero-pentameric complex with CYFIP1/2, NCKAP1/1 L, Abi1/2/3 and BRK1 called the WASF Regulatory Complex (WRC), which cooperatively regulates actin nucleation by WASF1/2/3. Activation of the WRC enables actin networking and provides the mechanical force required for the formation of lamellipodia and invadopodia. Although the WRC drives cell motility essential for several routine physiological functions, its aberrant deployment is observed in cancer metastasis and invasion. WASF3 expression is correlated with metastatic potential in several cancers and inversely correlates with overall progression-free survival. Therefore, disruption of the WRC may serve as a novel strategy for targeting metastasis. Given the complexity involved in the formation of the WRC which is largely comprised of large protein-protein interfaces, there are currently no inhibitors for WASF3. However, several constrained peptide mimics of the various protein-protein interaction interfaces within the WRC were found to successfully disrupt WASF3-mediated migration and invasion. This review explores the role of the WASF3 WRC in driving metastasis and how it may be selectively targeted for suppression of metastasis.
Insights
Wiskott-Aldrich syndrome protein family (WASF) complexes drive cancer metastasis. Disrupting these complexes with peptide mimics offers a novel strategy to suppress cancer invasion and improve survival.
Area of Science:
- Cell Biology
- Molecular Oncology
- Biochemistry
Background:
- Wiskott-Aldrich syndrome protein family (WASF) members regulate actin cytoskeleton dynamics, crucial for cell motility.
- The WASF Regulatory Complex (WRC), comprising WASF1/2/3 and other proteins, controls actin nucleation, lamellipodia, and invadopodia formation.
- Aberrant WRC activity is implicated in cancer metastasis and invasion, with WASF3 expression correlating with poor patient survival.
Purpose of the Study:
- To explore the role of the WASF3-containing WRC in driving cancer metastasis.
- To investigate the potential of targeting the WRC as a therapeutic strategy for suppressing cancer invasion.
- To review current approaches for disrupting WRC function, particularly peptide mimics.
Main Methods:
- Review of existing literature on WRC function, cancer metastasis, and therapeutic strategies.
- Analysis of the protein-protein interactions within the WRC.
- Evaluation of peptide mimics designed to disrupt WRC-mediated cell migration and invasion.
Main Results:
- The WRC, particularly WASF3, plays a significant role in promoting cancer cell motility, invasion, and metastasis.
- Disruption of WRC function can inhibit cancer cell migration and invasion.
- Constrained peptide mimics targeting WRC interfaces have shown efficacy in preclinical models.
Conclusions:
- The WRC represents a promising therapeutic target for inhibiting cancer metastasis.
- Targeting protein-protein interactions within the WRC using peptide mimics is a viable strategy.
- Further research into WRC inhibitors could lead to novel anti-metastatic therapies.
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