Pancreatic cancer (PaCa), one of the most lethal cancers among all malignancies, is characterized by aggressive local invasion and metastatic spread, with a post-diagnosis survival rate of only 7% over 5 years.
Tumour dissemination and metastasis requires cancer cells to access the vasculature; firstly, tumours can gain access by promoting endothelial cell-mediated angiogenesis to create new vessels, and secondly, through a process independent of endothelial vessels by forming vessel-like structures lined by cancer cells, a process known as vasculogenic mimicry (VM). VM has been linked to increased tumour metastasis and poor prognosis in many solid tumours. Due to the hypoxic nature of PaCa, there is a predisposition for the formation of VM in order to gain access to the blood supply. Accordingly, the literature reports that PaCa cells have a robust VM capability.
Our laboratory has identified a single cell surface molecule, desmoglein-2 (DSG2), which regulates vascular integrity, promotes cancer progression, regulates cell adhesion and promotes VM in skin cancer. Interestingly, studies have also reported that DSG2 promotes pancreatic cancer progression.
The aim of this study is to investigate the role of DSG2 in PaCa. Preliminary data suggests that PaCa cell lines BxPC-3 and AsPC-1 undergo VM and their VM capacity is inhibited significantly with DSG2 knock down. In a surprising finding, we also observed that DSG2 is involved in promoting PaCa cell survival in a cell specific manner where epithelial cancer cells (BxPC-3) undergo cell death with DSG2 knockdown, whereas the mesenchymal cancer cells (AsPC-1) do not appear to utilise DSG2 for cell survival. Taken together, this finding suggests a unique opportunity to target, and kill, PaCa in its early stages prior to mesenchymal transition. If our hypothesis is correct, a future aim of this project is to inhibit DSG2 in vivo by utilising our DSG2 targeting-siRNA loaded porous silicon nanoparticles as a potential therapeutic to combat PaCa.