Cancer research in IB3 – models, mice and microfluidics

I will briefly describe collaborative projects to develop new 3D bioprinted cancer models and to enrich and detect tumour DNA in blood samples from cancer patients. However, as these projects will be covered in other talks by their lead researchers, I will spend much of my seminar describing two projects which are currently being written up for publication, using genetically modified mouse models to define the functions of the PTEN tumour suppressor.

Loss of function of the PTEN tumour suppressor is one of the most common events driving aggressive prostate cancers and biochemically, PTEN is a lipid phosphatase which opposes the activation of the oncogenic PI3K-AKT signalling network. However, PTEN also has additional potential mechanisms of action, including protein phosphatase activity, with uncertain significance in cancer. Having previously developed a mutant enzyme, PTEN Y138L, which selectively lacks protein phosphatase activity, here we have used genetically modified mice to remove either the full function of PTEN in the prostate gland or selectively to remove protein phosphatase activity. We found that prostate adenocarcinoma, elevated proliferation and activation of AKT were only frequently observed when PTEN was fully deleted. The phenotypes observed in mice carrying a single allele of either wild-type Pten or PtenY138L in the prostate were very similar to each other, with common prostatic intraepithelial neoplasia (PIN) and very similar changes in gene expression. However, the latter group, lacking PTEN protein phosphatase activity additionally showed evidence of lymphocyte invasion by histology and an increased immune cell gene expression signature. Comparison with other studies of gene expression changes caused by full loss of PTEN in the murine prostate identify a small number of genes (<50) which were significantly and consistently altered in studies of young (6-12 weeks of age) animals including Nkx3.1, Tnf and Cd44 as well as several recognised prostate cancer biomarkers. Our data show that the protein phosphatase activity of PTEN is not required for tumour suppression in the prostate. We provide further insight into tumour development in the prostate driven by loss of PTEN function and its correlation with the loss of PTEN lipid phosphatase activity and the activation of AKT.”