The Role of WAVE2 Signaling in Cancer

The Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)—WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.

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Adaptation of the Golgi Apparatus in Cancer Cell Invasion and Metastasis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.806482 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sarah Bui ◽

Isabel Mejia ◽

Begoña Díaz ◽

Yanzhuang Wang

Keyword(s):

Golgi Apparatus ◽

Cancer Cell ◽

Cell Invasion ◽

Critical Role ◽

Cell Communication ◽

Cell Physiology ◽

Cancer Cell Invasion ◽

Invasion And Metastasis ◽

And Migration ◽

And Function

The Golgi apparatus plays a central role in normal cell physiology by promoting cell survival, facilitating proliferation, and enabling cell-cell communication and migration. These roles are partially mediated by well-known Golgi functions, including post-translational modifications, lipid biosynthesis, intracellular trafficking, and protein secretion. In addition, accumulating evidence indicates that the Golgi plays a critical role in sensing and integrating external and internal cues to promote cellular homeostasis. Indeed, the unique structure of the mammalian Golgi can be fine-tuned to adapt different Golgi functions to specific cellular needs. This is particularly relevant in the context of cancer, where unrestrained proliferation and aberrant survival and migration increase the demands in Golgi functions, as well as the need for Golgi-dependent sensing and adaptation to intrinsic and extrinsic stressors. Here, we review and discuss current understanding of how the structure and function of the Golgi apparatus is influenced by oncogenic transformation, and how this adaptation may facilitate cancer cell invasion and metastasis.

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EB1 Restricts Breast Cancer Cell Invadopodia Formation and Matrix Proteolysis via FAK

Cells ◽

10.3390/cells10020388 ◽

2021 ◽

Vol 10 (2) ◽

pp. 388

Author(s):

Brice Chanez ◽

Kevin Ostacolo ◽

Ali Badache ◽

Sylvie Thuault

Keyword(s):

Breast Cancer ◽

Cancer Cell ◽

Cell Invasion ◽

Focal Adhesions ◽

Matrix Degradation ◽

Cancer Cell Invasion ◽

Wild Type ◽

Spatial Regulation ◽

Invadopodia Formation

Regulation of microtubule dynamics by plus-end tracking proteins (+TIPs) plays an essential role in cancer cell migration. However, the role of +TIPs in cancer cell invasion has been poorly addressed. Invadopodia, actin-rich protrusions specialized in extracellular matrix degradation, are essential for cancer cell invasion and metastasis, the leading cause of death in breast cancer. We, therefore, investigated the role of the End Binding protein, EB1, a major hub of the +TIP network, in invadopodia functions. EB1 silencing increased matrix degradation by breast cancer cells. This was recapitulated by depletion of two additional +TIPs and EB1 partners, APC and ACF7, but not by the knockdown of other +TIPs, such as CLASP1/2 or CLIP170. The knockdown of Focal Adhesion Kinase (FAK) was previously proposed to similarly promote invadopodia formation as a consequence of a switch of the Src kinase from focal adhesions to invadopodia. Interestingly, EB1-, APC-, or ACF7-depleted cells had decreased expression/activation of FAK. Remarkably, overexpression of wild type FAK, but not of FAK mutated to prevent Src recruitment, prevented the increased degradative activity induced by EB1 depletion. Overall, we propose that EB1 restricts invadopodia formation through the control of FAK and, consequently, the spatial regulation of Src activity.

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Quantitative real-time imaging of molecular dynamics during cancer cell invasion and metastasis in vivo

Cell Adhesion & Migration ◽

10.4161/cam.3.4.9460 ◽

2009 ◽

Vol 3 (4) ◽

pp. 351-354 ◽

Cited By ~ 11

Author(s):

Paul Timpson ◽

Alan Serrels ◽

Marta Canel ◽

Margaret C. Frame ◽

Valerie G. Brunton ◽

...

Keyword(s):

Molecular Dynamics ◽

Real Time ◽

Cancer Cell ◽

Cell Invasion ◽

Cancer Cell Invasion ◽

Invasion And Metastasis ◽

Real Time Imaging

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The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors

The Journal of Cell Biology ◽

10.1083/jcb.200510115 ◽

2006 ◽

Vol 173 (3) ◽

pp. 395-404 ◽

Cited By ~ 178

Author(s):

Weigang Wang ◽

Ghassan Mouneimne ◽

Mazen Sidani ◽

Jeffrey Wyckoff ◽

Xiaoming Chen ◽

...

Keyword(s):

Cell Motility ◽

Cell Invasion ◽

Actin Polymerization ◽

Cancer Cell Invasion ◽

Invasion And Metastasis ◽

Over Expression ◽

Cell Biol ◽

Tumor Cell Motility ◽

New Strategies

Understanding the mechanisms controlling cancer cell invasion and metastasis constitutes a fundamental step in setting new strategies for diagnosis, prognosis, and therapy of metastatic cancers. LIM kinase1 (LIMK1) is a member of a novel class of serine–threonine protein kinases. Cofilin, a LIMK1 substrate, is essential for the regulation of actin polymerization and depolymerization during cell migration. Previous studies have made opposite conclusions as to the role of LIMK1 in tumor cell motility and metastasis, claiming either an increase or decrease in cell motility and metastasis as a result of LIMK1 over expression (Zebda, N., O. Bernard, M. Bailly, S. Welti, D.S. Lawrence, and J.S. Condeelis. 2000. J. Cell Biol. 151:1119–1128; Davila, M., A.R. Frost, W.E. Grizzle, and R. Chakrabarti. 2003. J. Biol. Chem. 278:36868–36875; Yoshioka, K., V. Foletta, O. Bernard, and K. Itoh. 2003. Proc. Natl. Acad. Sci. USA. 100:7247–7252; Nishita, M., C. Tomizawa, M. Yamamoto, Y. Horita, K. Ohashi, and K. Mizuno. 2005. J. Cell Biol. 171:349–359). We resolve this paradox by showing that the effects of LIMK1 expression on migration, intravasation, and metastasis of cancer cells can be most simply explained by its regulation of the output of the cofilin pathway. LIMK1-mediated decreases or increases in the activity of the cofilin pathway are shown to cause proportional decreases or increases in motility, intravasation, and metastasis of tumor cells.

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