Project Title: Investigation of mechanisms regulating
phosphoinositide 3-kinase expression in pancreatic cancer
Research Aims: Studies using pancreatic cancer tissue and pancreatic tumour cell lines have identified several genetic and epigenetic disturbances that are common in human pancreatic cancer. Even so, the molecular mechanisms driving this aggressive neoplasm remain poorly understood. In our previous work we have found that human pancreatic cancer tissue specifically expresses high levels of the signalling molecule PI3K/p110gamma and we demonstrated that p110gamma is indeed imperative for the proliferation of pancreatic cancer cells. In addition, our data suggested that p110gamma is involved in pancreatic cancer chemoresistance, since the level of p110gamma is markedly upregulated upon treatment with Gemcitabine.
Our data indicate that p110gamma expression is silent in the normal pancreas and then turned on in pancreatic cancer. This prompts us to investigate how this works. Firstly, we plan to look at changes on the genetic level. Secondly, we think that the evident upregulation might be induced by other cells in the cancerous pancreas, for example the stromal cells that are common in the tissue. Therefore we plan to analyse cell growth and p110gamma level in a complex three dimensional system, including different relevant cell types. Thirdly, even though so far there are poorly understood mutations in the p110gamma gene, we have preliminary data that there might be mutations similar to the ones found in the p110alpha oncogene. Therefore, we plan to screen tissues to see if this is the case. Lastly, our recent finding regarding p110gamma upregulation by Gemcitabine treatment is very interesting and we want to test if targeting p110gamma together with Gemcitabine could improve the efficacy of the therapy. Recent results from cell lines indicate that co-treatment is beneficial and thus prompts us to test this in an appropriate mouse model which is similar to human pancreatic cancer.