Investigating the roles of Fascin and Rac1 in cell migration, invasion and metastasis

Li, Ang (2011) Investigating the roles of Fascin and Rac1 in cell migration, invasion and metastasis. PhD thesis, University of Glasgow.

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Cell migration and invasion is a central process in embryonic development, wound healing and immune responses. Errors during this process have serious consequences, including mental retardation, vascular disease, tumor formation and metastasis. An understanding of the mechanism by which cells migrate and invade may lead to the development of novel therapeutic strategies for controlling, for example, cancer metastasis.

Fascin is an actin-bundling protein involved in filopodia assembly and cancer invasion and metastasis of multiple epithelial cancer types. In this thesis, I have investigated the role of fascin in invadopodia formation, which are invasive finger-like protrusions that cancer cells use to invade into and degrade extracellular matrix. I demonstrated that fascin and its actin bundling activity are required for the assembly of the actin cytoskeleton at invadopodia as well as for the degradation of matrix. Fascin is a very stable component of invadopodia and its presence enhance the stability of actin structures at invadopodia. Furthermore, fascin is required for invasive migration into collagen I-Matrigel gels particularly in cell types that use an elongated mesenchymal type of motility in 3D. These data provide a potential molecular mechanism for how fascin increases the invasiveness of cancer cells.

During embryogenesis, melanoblasts proliferate and migrate ventrally through the developing dermis and epidermis as single cells. In the second part of this thesis, I examined the importance of small Rho GTPase Rac1 on melanoblast migration during development. I demonstrate that targeted deletion of Rac1 in the melanoblasts of developing mice causes defects in migration, cell cycle progression and cytokinesis. Rac1 null cells migrate markedly less efficiently, but surprisingly global steering, crossing the dermal/epidermal junction andhoming to hair follicles are normal. Melanoblasts navigate in the epidermis using two classes of protrusion: short stubs and long pseudopods. Short stubs are driven by actin assembly, but unexpectedly are independent of Rac1, Arp2/3 complex, myosin or microtubules. Rac1 positively regulates
the frequency of initiation of long pseudopods, which promote migration speed and directional flexibility. Scar/WAVE and Arp2/3 complex drive actin assembly for long pseudopod extension, which is also microtubule dependent. Myosin contractility balances the extension of long pseudopods by effecting retraction and allowing force generation for movement through the complex 3D epidermal environment. In addition, I demonstrated that expression of activated N-Ras did not affect migration and proliferation of melanoblast during embryogensis. However, Rac1 is required for constitutively active N- Ras induced dermal melanocytes survival in mice.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: R Medicine > R Medicine (General)
Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Supervisor's Name: Machesky, Prof Laura
Date of Award: 2011
Depositing User: Mr Ang Li
Unique ID: glathesis:2011-2849
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 21 Sep 2011
Last Modified: 10 Dec 2012 14:00

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