Scar/WAVE complex suppresses cell invasion and cancer cell transformation

Tang, Haoran (2012) Scar/WAVE complex suppresses cell invasion and cancer cell transformation. PhD thesis, University of Glasgow.

Abstract

The mechanisms by which cancer cells hijack the actin cytoskeleton to invade and disseminate to distant sites of metastasis remains one of the great frontiers in cancer research. Many actin-regulating proteins have been identified to be important in cancer cell invasion and metastasis. However the role of a major actin assembly promoting complex, Scar/WAVE regulatory complex (WRC) in cancer cell invasion is poorly understood.

WRC has a well-known motility-promoting role in 2D planar cell migration, but a recent study on human epithelial cancers suggests WRC may be anti-invasive in vivo. To investigate the controversy, human epithelial cancer cells with reduced WRC expression were tested in multiple 3D cell motility assays. Interestingly, WRC demonstrates a robust anti-invasive role in these exciting experiments.

To understand how loss of WRC promotes invasion, the molecular mechanism is investigated. N-WASP is the other major actin assembly promoting protein. Unlike WRC, N-WASP is interestingly not required for 2D planar cell migration, but is important for motility in 3D. The interplay of the two major actin assembly promoting proteins has not been explored in 3D cell motility. I report here that loss of WRC promotes hyper-activation of focal adhesion kinase that leads to N-WASP accumulation and activation at the invasive front. This chain of events results in enhanced invasion providing a molecular mechanism of WRC’s anti-invasive function.

In addition to this FAK-N-WASP core mechanism, I also identified a novel pro- invasive role of HSPC300 independently of WRC. Loss of WRC possibly releases free HSPC300 that could subsequently interact with and regulate N-WASP activation during invasion providing a potential direct molecular link between the two proteins. Furthermore, WRC also supresses focal adhesion kinase mediated cell transformation and tumour formation in vivo.

In this thesis I therefore demonstrate novel anti-invasion and anti-tumourigenesis functions of WRC. I also show how a novel WRC binding protein, NHS, could negatively regulate WRC function.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Scar/WAVE complex, cell migration, invasion, cancer, FAK, collagen gel
• Subjects: Q Science > QP Physiology; Q Science > Q Science (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Machesky, Prof. Laura
• Date of Award: 2012
• Depositing User: Mr Haoran Tang
• Unique ID: glathesis:2012-3633
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 12 Oct 2012
• Last Modified: 04 Feb 2014 09:55
• URI: https://theses.gla.ac.uk/id/eprint/3633