Andrew Gilmore, BA PhD

In all multicellular organisms it is essential that cells only grow and function in the correct context within a tissue or organ. Signals from the extracellular matrix (ECM) provide these positional cues,which are essential for maintaining tissue integrity. Appropriate ECM contact not only allows cells to grow and differentiate, but it also functions as a survival factor. Cells that do not receive the correct information from the ECM undergo apoptosis, a genetically controlled suicide programme by which damaged, displaced or unwanted cells are removed. Apoptosis is an extremely efficient process, deleting cells quickly and efficiently whilst avoiding harmful inflammatory responses. The importance of ECM dependent cell survival is seen in the development of invasive carcinoma, one of the hallmarks of which is the ability of cancer cells to metastasise to distant sites within the patient.We are trying to understand how ECM derived signals regulate apoptosis,with a long term goal of identifying how this is abrogated in cancer cells.

The scientific story

Apoptosis controlled by members of the Bcl-2 protein family,which act by forming pores on the outer membrane of mitochondria. These pores release a variety of factors, including cytochrome c and SMAC/Diablo,which then directly induce cell death.We have found that one member of the Bcl-2 family, Bax, becomes activated in cells following the loss of ECM derived survival signals. In adherent cells, Bax is predominantly found in the cytosol, but following loss of adhesion it accumulates on the outer mitochondrial membrane (OMM). Bax trafficking to and from mitochondria appears to be regulated by Focal Adhesion Kinase (FAK), a tyrosine kinase activated by integrin-mediated attachment to ECM. FAK is up regulated in the majority of breast cancers, including early stages of the disease. Thus, dysregulation of FAK may contribute how cancer cells become insensitive to the ECM derived positional controls that maintain normal epithelia integrity.We are currently establishing an number of models to determine how FAK alters the mammary epithelial phenotype.

Once on the OMM, Bax undergoes a conformational change and assembles into a multimolecular complex that may form the cytochrome c releasing pores. At early points along this pathway, cells can be rescued from apoptosis if survival signals are restored, but prolonged detachment results in cells being committed to die. Our results indicate that changes in Bax may control a survival "check point",which may have fundamental consequences for controlling cell fate at a molecular level.We have recently identified regulatory enzymes controlling this commitment step, and are trying to elucidate how this checkpoint functions.

Current work is aimed at understanding how adhesion signals control Bax and apoptosis commitment, using a combination of molecular cell biology, biochemistry and cell imaging.

We have three broad goals for this work.

1. Defining how adhesion dependent signalling controls Bax activation in normal cells.

2. Identifying the molecular basis for the apoptosis "check point" on mitochondria.

3. Determining how FAK may contribute to breast cancer progression.

Recent key publications

Schellenberg, B., Wang, P., Keeble, J.A., Rodriguez-Enriquez, R., Walker, S., Owens, T., Foster, F., Tanianis-Hughes, J., Brennan, K., Streuli, C.H., Gilmore, A.P. (2013). Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming. Mol Cell. 23, 1287-93. PubMed

Owens, T.W., Valentijn, A.J., Upton, J.P., Keeble, J., Zhang, L., Lindsay, J., Zouq, N.K., and Gilmore, A.P. (2009). Apoptosis commitment and activation of mitochondrial Bax during anoikis is regulated by p38MAPK. Cell Death Differ. 16, 1551-62. PubMed .

Zouq, N.K., Keeble, J.A., Lindsay, J., Valentijn, A.J., Zhang, L., Mills, D., Turner, C.E., Streuli, C.H., and Gilmore, A.P. (2009) FAK engages multiple pathways to maintain survival of fibroblasts and epithelia - differential roles for paxillin and p130Cas. J Cell Sci. 122, 357-67. PubMed

Full list of publications