Regulation of cancer cell plasmin formation by S100A10

Working at a complex, molecular level, Dr Waisman will investigate how a specific protein in tumour cells, newly implicated in the spread of cancers, controls the production of enzymes - called plasmin - that are key to this spread. If he can understand how the process works, antibodies can be developed to stop the protein from functioning, adding to doctors' toolkits for cancer treatments. Project summary: A tumour cell becomes potentially deadly when it acquires the ability to a) escape the restrictions imposed upon it by neighbouring cells and surrounding tissue, b) invade the surrounding tissue, c) escape into circulation and d) start growing in other areas of the body. It is this property of a cancer cell that is responsible for the majority of cancer deaths. The malignant property of tumour cells is dependent, in part, on the activation of enzymes that act as molecular scissors and therefore allow the cancer cells to destroy any obstacle in their path. The molecular scissor-type enzymes, which are activated at the cell surface, are called proteinases. Plasmin is one of the key proteinases that participate in the deadly spread of cancer cells. This laboratory has identified a protein known as S100A10 on the surface of tumour cells, and Dr Waisman's team has proposed that this protein helps to control how much plasmin tumour cells make. They plan to investigate the role of S100A10 in tumour growth, invasion and metastasis, and also determine if S100A10 is an important regulator of plasmin production by tumour cells and the host cells that support tumour development, the endothelial cells and macrophages. Previous research: This lab has shown that in the test-tube, S100A10 is a potent activator of plasmin formation. Most importantly, they demonstrated that knock-down (reduction) of S100A10 levels on the surface of human fibrosarcoma tumour cells blocks the capability of these tumour cells to produce plasmin. Furthermore, these tumour cells show reduced invasiveness,and either fail to form tumours or form only very small tumours in mice. Therefore, they have established a link between S100A10 levels on the surface of human fibrosarcoma cancer cells and the ability of these cells to produce plasmin and to form tumours. They have also generated preliminary data to show that mouse tumour cells grow slowly in mice that have been engineered not to produce S100A10 i.e. the gene for S100A10 has been knocked-out (p11KO mice). This suggests that tumour-associated cells that originate from the mouse may also require S100A10 to nurture the growth of the tumours. Project description: This team proposes to establish how the blocking of expression of S100A10 influences tumour growth and metastasis. They will begin by measuring the tumour and metastatic growth of three model mouse tumour cells in the normal and p11KO mice. Tumour and metastatic growth will be determined by both traditional methods as well as state-of-the-art imaging techniques. These will establish if the cells that normally nourish and help maintain the tumour require S100A10 for this function. They will also engineer mouse and human tumour cells not to produce S100A10 (p11KD cells) and monitor their ability to form tumours and metastases in normal and p11KO mice. They suspect that the primary function of S100A10 is facilitation of plasmin production. They therefore propose to compare the ability of normal and p11KD tumour cells and also normal and p11KO tumour support cells (endothelial cells and macrophages) to produce plasmin. Impact and relevance: The concept that S100A10 regulates tumour growth and metastasis is novel. If they establish a role for S100A10 in tumour and metastatic growth then they would develop specific antibodies to block its function. This work therefore has the potential to provide new strategies for cancer treatment.