In my lab, we are interested in cell communication, so how cells, one lot of cells will secrete ligands that then bind to another set of cells, their receptors, and change their behaviour. The group of ligands that we are particularly interested in are called the TGF-β superfamily. What I am going to talk about today is TGF-β and its role in cancer. It’s been known for a very long time to have both tumour suppressive roles and tumour promoting roles. The first bit of my talk, I’m going to discuss the issue of whether cells have to lose the tumour suppressive effects of TGF-β in order to gain tumour promoting effects. We’ve been using intravital imaging in mice and show that TGF-β promotes cell motility in the primary tumour, this allows the tumour cells to metastasise but then when they get to the lung they lose that TGF-β availability and so they then can grow at the sites of metastasis.

That work led us to start to think about how cells respond long term to these ligands and we had known in tumours you tend to see very sustained responses. So, we’ve been working in vitro systems to try and understand how cells respond long term and realise that actually cells normally if they have a long exposure to TGF-β become very repressed to or resistant to TGF-β responses. So, we did some screens to try and work out how cells, cancers cells, might get rewired in order to respond long term to TGF-β. And I’m going to talk about the results from those screens.

What drives the gene activation?

It is probably the stromal cells so fibroblasts, cancer associated fibroblasts, that initially secrete TGF-β and then that sets up a positive feedback loop where the tumour cells then also make TGF-β but once they get away from the primary tumour they lose that source of TGF-β and then when they get to the lung there is no TGF-β there so that’s why they can then grow.