Short biography

Alan Hall studied chemistry at the University of Oxford and received his PhD of Chemistry in 1977 at Harvard University in Boston. For his postdoctoral research he joined the Department of Molecular Biology at the University of Edinburgh and the Institute of Molecular Biology at the University of Zurich. In 1981, he became a group leader at the Chester Beatty Laboratories of the Institute of Cancer Research in London. Since 1993, he is a professor of Molecular Biology at the University College, London, and since 2001, the Director of the Medical Research Council Laboratory for Molecular Cell Biology & Cell Biology Unit. He received the Feldberg Prize in 1993. He is a member of EMBO and a Fellow of the Royal Society.

Cell biology of tumor invasion

The development of human cancer involves the accumulation of many genetic changes that alter the behaviour of normal cells. Over the last twenty years, many cancer causing genes have been identified and the best understood of these affect cell proliferation. For example, mutations have been found in genes that encode proteins involved in signal transduction pathways, including plasma membrane receptors, cytoplasmic kinases and regulatory GTPases, as well as in cell cycle control, such as cyclins and transcription factors. However, the ability of a cell to divide uncontrollably is not sufficient for tumour growth – changes that promote further genetic instability, overcome cell death programmes, or induce angiogenesis (blood vessel formation) are also required. Even so, the formation of a growing tumour mass is only one aspect of the human disease and a much more life threatening metastatic phase can follow, where individual cells dissociate and migrate away from the original tumour and invade neighbouring tissues and stroma. They then enter the blood or lymph vasculature, are transported around the body and form disseminated, secondary tumours.

During the first phase of tumour growth, interactions between tumour cells are maintained and often resemble those seen in the corresponding normal tissue. In epithelial tumours (the most common human cancers), cadherin-based cell-cell junctions are still present and contribute to the maintenance of a physically-distinct tumour mass. The genetic steps that facilitate metastatic progression are poorly understood, but in part they cause a breakdown of cell-cell interactions within the primary tumour and an increase in migratory activity resulting in tumour cells escaping and invading into neighbouring tissues (Figure 1).

Figure 1: Left panel: View from the top of an epithelial cell monolayer. Cadherin-based cell-cell junctions (in red) are visualized by microscopy. Middle panel: View from the side of the same epithelial cell monolayer. The outline of one cell in the monolayer has been marked with a dotted white line. Right Panel: Schematic view from the side of an epithelial cell monolayer. Cadherin-based cell-cell junctions (red) provide strong connections between cells to maintain the physical integrity of tissues. They also generate cell polarity, where each cell has a top (black) and a side/bottom (white). Disruption of the junctions occurs during the metastatic phase of cancer progression, allowing cells to move away. The nucleus is shown in grey

Over the last fifteen years, Alan Hall’s laboratory has been working on the Rho GTPase family of proteins. Alan Hall and his colleagues first reported two distinct signal transduction pathways through which these proteins affect the organization of the actin cytoskeleton. Rho itself regulates the assembly of contractile actin:myosin filaments within a cell, while Rac another member of the family, promotes actin polymerization and the formation of filaments at the outermost edges of a cell. As shown by Alan Hall’s and numerous other groups, combinations of these two activities regulate the shape and migratory properties of animal cells (Figure 2).

Figure 2: Actin filaments are visualized by microscopy (white). Top left : A non-migratory cell in the absence of a stimulus. The cell contains very little organized actin. Top right. The same cell stimulated to activate Rho. This cell has assembled actin:myosin filaments traversing the cell. These generate contractile forces pulling the cell edges inwards. Bottom left. The same cell stimulated to activate Rac. Actin filaments are assembled just underneath the cell periphery, pushing the cell edges outwards. Bottom right. A still taken from a movie of a cell migrating in the direction shown. The front of the cell is being pushed forward by Rac-induced actin filament formation and the cell body and cell rear are being squeezed forward by Rho-induced contractile forces.

More recently, other functions have been identified for Rho GTPases, including a role in promoting cell-cell adhesion in non-motile cells. This remarkable ability to regulate seemingly opposing activities is intriguing and presumably reflects the different biochemical and biological contexts in which they act. Since tumour invasion requires inhibition of cell-cell adhesion and stimulation of cell migration, there is a great deal of interest in the contributions made by Rho GTPases and their signal transduction pathways to the metastatic phenotype.

Alan Hall and his colleagues are using normal and tumour-derived cells, in tissue culture assays, to examine the function of Rho GTPases during cell migration and epithelial cell-cell junction assembly. From their recent experiments, they have identified two proteins, Dlg and APC, which are required for directional migration of normal cells. There are two striking features arising from these observations. First, both APC and Dlg are tumour suppressor proteins, i.e. they normally inhibit cell proliferation and in fact, the APC gene is mutated in many human cancers. Second, Dlg has previously been shown to promote cell-cell adhesion in epithelial cells. This work suggests some unexpected, common mechanisms linking the process of cell migration to both cell-cell adhesion and cell proliferation. Alan Hall and his colleagues aim now at understanding the pathways by which Rho GTPases control migration and cell-cell adhesion in normal cells and at seeing how these are altered in invasive human cancers.

Professor Alan Hall
Professor of Molecular Biology
Director
MRC Laboratory for Molecular Cell Biology & Cell Biology Unit
University College London
Gower Street
UK – LONDON WC1E 6BT

Tel: +44 20 7679 7909
Fax: +44 20 7679 7804
E-mail:  alan.hall@ucl.ac.uk
Website: http://www.ucl.ac.uk/lmcb/