Modelling Pancreatic Cancer to Study the Effects of Wnt11 and miRNAs on Epithelial-Mesenchymal Transition (EMT)

We propose to study the involvement of the protein Wnt-11 in pancreatic cancer (PC). Wnt-11 is normally made by cells in the developing embryo but, as is often the case, tumour cells find ways to use developmentally important proteins to help them survive and grow. It has been accepted that PC is one of the most aggressive malignancies and has a 5-year survival of less than 4%, which has remained unchanged over the last 40 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker.
Aims: Taking our previous knowledge and experiences together, we propose to study the role of Wnt-11 in pancreatic cancer and its involvement in EMT. miRNAs are small noncoding, endogenous, single-stranded RNAs that are pivotal regulators of posttranscriptional gene expression. It has been demonstrated that miRNA expression is related to cell proliferation, invasion and chemoresistance of PC, and some miRNAs act as a regulator for the EMT of tumour cells. EMT is characterised by loss of E-cadherin expression and is related to the invasive behaviour of cancer cells. We, and others, have previously reported that Wnt-11 is linked to EMT, and EMT may be partial, incomplete, or even reversible. Recent work demonstrates that EMT results in suppression of cancer cell proliferation and suppression of drug transporter and concentrating proteins, therefore inadvertently protecting EMT positive cells from anti-proliferative drugs such as gemcitabine, which is a standard therapy for most patients. The resistance of the chemotherapy may also explain higher metastatic prognosis. The field of 3D cancer tumouroids is driven by the need to interrogate genetic and cellular events in real time to understand cancer biology, and as platforms to assess drug responses in a manner relevant to the clinic. Therefore we will be studying potential miRNAs, EMT and Wnt-11 interaction by using 3D cancer models.
Impact: Our data will give a better understanding of the role of Wnt-11 and certain miRNAs in PC and its metastasis. These next-generation tumouroids will provide meaningful data on pancreatic cancer responsiveness to chemotherapeutic agents and have real potential in part-replacing animal models for longitudinal cancer biology investigations and drug screening. It will thus provide faster and clinically meaningful data, transforming pre-clinical research.
The student will take part in the University Graduate School and Faculty Doctoral Research Development Programme; in addition to these training programmes and the subject specific skills listed above, the student will gain important transferable skills (e.g. presentation skills, scientific writing and employability skills) to aid in future career progression. The student will be encouraged to join learned societies (e.g. the British Association for Cancer Research, European Association for Cancer Research), which provide excellent support for students in terms of training workshops and regular meetings to disseminate and publish their research.