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Research

The central interest of the laboratory is in cell-matrix adhesion processes and their roles in extracellular matrix organisation and the regulation of intracellular signaling and cell protrusions. We study molecular mechanisms of these processes in health and disease.

Fascin-based protrusions and their role in carcinoma cell migration and metastasis

Tumour cell migration and metastasis are major causes of mortality for carcinoma patients and remain intractable problems for disease management. Migrating tumour cells have low proliferation and tend to be resistant to conventional therapies. We are studying the role in carcinomas of an actin-bundling protein, fascin-1, that contributes to the assembly of cell protrusions and directional cell migration. Fascin-1 has emerged as a clinically relevant biomarker for the most aggressive carcinomas from multiple tissues and is interesting as a prospective therapeutic target because it is absent from most normal epithelia. We have demonstrated that fascin-1 mediates carcinoma cell migration and invasion in vitro and contributes to metastasis of tumour xenografts. Current projects are to study signaling mechanisms that regulate fascinís actin-bundling activity in migration and metastasis and to assess the suitability of fascin-1 as a potential novel therapeutic target, through experimental and epidemiological approaches.

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Some recent papers

Impact story - Understanding Cells (PDF, 414kB)

Thrombospondins and their roles in Extracellular Matrix

Thrombospondins are extracellular, oligomeric, calcium-binding glycoproteins with roles in angiogenesis, vascular biology, connective tissues, immune response and synaptogenesis in mammals. Many thrombospondins are transient components of the extracellular matrix during cell migration or tissue remodeling. Thrombospondins have a complex domain organization and are most highly conserved in their C-terminal regions. We are currently analysing the mechanisms by which thrombospondins become deposited into the extracellular matrix through interactions of the C-terminal region with cell surfaces and other matrix components. This project focuses on thrombospondin-1, that is up-regulated in blood vessel walls after injury or in atherosclerotic lesions and acts to promote smooth muscle cell migration and proliferation. In related projects we are examining the evolution of thrombospondins and their conserved roles within the extracellular matrix and extracellular matrix organisation.

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Some recent papers


The Muskelin/RanBP9 complex/CTLH complex

Muskelin and RanBP9 are co-associated proteins whose knockdown phenotypes in mammalian cells demonstrate functional roles in cell morphology regulation. RanBP9 mediates association with a widely-expressed protein complex referred to as muskelin/RanBP9/CTLH complex. A homologous complex in budding yeast functions in proteosomal and vacuolar degradation of specific target proteins. Selective protein degradation is an important regulatory mechanism in cells, and aberrations contribute to human disease. Fundamental aspects of the organisation, regulation and roles of muskelin/RanBP9/CTLH complex in mammalian cells remain unknown. We are examining the organisation and activity of the complex under homeostatic conditions and under low glucose cell stress conditions. Current projects are investigating the hypothesis that mammalian muskelin/RanBP9/CTLH complex regulates degradation of specific target proteins that include cytoskeletal and adhesion proteins.

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Recent papers