Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal of all cancer types. We have discovered that desmoglein-2 (DSG2), a cell surface-expressed cadherin is highly expressed in PDAC cells. In silico data indicate that PDAC patients with high levels of DSG2 are more likely to succumb to disease within the first two years of diagnosis. Our hypothesis is that DSG2 is an under-appreciated contributor to PDAC that can be targeted.
Our in vitro data showed that reducing expression of DSG2 significantly attenuated PDAC cell migration and invasion. Additionally, in an orthotopic xenograft mouse model, PDAC cells with stable knock down of DSG2 via short-hairpin RNA resulted in a significantly reduced tumour burden and liver metastasis compared to the control cohort. DSG2kd tumours also presented with reduced levels of collagen, tumour vasculature and cancer associated fibroblasts in the tumour microenvironment (TME), indicating that DSG2 has a modulatory effect on the TME of PDAC.
To understand the molecular mechanism behind our findings, we completed a phospho-proteomic/signalling analysis of PDAC cells ±DSG2 using a reverse-phase protein array. These experiments revealed that DSG2 modulates a broad array of proteins associated with cancer cell adhesion, migration, proliferation, and signalling. In particular, DSG2kd appears to have a modulatory effect on pro-tumourigenic and pro-metastatic signalling pathways such as gene regulation, integrin, and survival pathways.
To conclude, we have identified a potentially new target in PDAC for improved patient survival in the hope to one day making PDAC a more manageable disease.