Preliminary data from our lab revealed a mucin-like glycoprotein podoplanin (PDPN) suppresses cyclooxygenase (COX)-2 expression. COX-2 is an enzyme involved in catalysing the formation of prostaglandins, a group of lipids that facilitate various physiological and pathological processes. I am particularly interested in prostaglandin E2 (PGE2) as it can mediate inflammatory and immune responses. COX-2 is overexpressed in many cancers and associated with tumour progression, however existing data regarding roles of PGE2 in the tumour microenvironment (TME) are conflicting. Some show PGE2 can promote dendritic cell (DC) maturation and immune infiltration, while others suggest it impedes T cell activity and promotes tumour proliferation.
PDPN is expressed on resident fibroblast reticular cells (FRCs) in the lymph node (LN) and is also upregulated in many cancers and cancer-associated fibroblasts. PDPN binding to a CLEC-2 receptor on DCs triggers LN expansion during the immune response. This contact also upregulates COX2 expression, although we do not understand the underlying mechanisms. The first part of my project therefore focuses on investigating the signalling pathways linking PDPN-CLEC-2 interaction with COX-2 transcriptional regulation, while the second looks in cancer to determine whether the PDPN-COX-2-PGE2 axis can be targeted in vivo to alter the inflammatory and immunosuppressive niche.