Poster Presentation 35th Lorne Cancer Conference 2023

Inhibiting stromal fibrosis in pancreatic cancer (#107)

Sakshi Arora 1 , Mary Vail 1 , Stacey Allen 1 , Andrew Scott 1 , Peter Janes 1
  1. Olivia newton john cancer research institute, Heidelberg, VICTORIA, Australia

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies and a prominent cause of cancer-associated deaths. Owing to the failure of early detection and therapeutic efficacy, it has an overall survival rate of only 8%. PDAC is characterised by a rich desmoplastic stroma, with a dense extracellular matrix (ECM) produced by specialised, myofibroblast-like, cancer-associated fibroblasts (myCAFs) which are associated with increased tumour cell survival, epithelial-to-mesenchymal transition (EMT), angiogenesis, immune suppression, and resistance to therapy. Inhibiting PDAC fibrosis could thus significantly improve therapeutic response. Eph receptors and their cell-bound ephrin ligands control cell-cell interactions guiding vascular and neural patterning during normal development and re-emerge in tumours and the TME. They are thus recognised drug targets. EphA3 is over-expressed in a range of solid tumour types, and we previously found this expression was not only in tumour cells, but more commonly in supportive stromal and vascular tissues in human tumour samples and mouse xenografts. We have also recently identified EphA3 to be expressed on mesenchymal stromal cells/CAFs in human PDAC and a mouse PDAC model. To investigate whether EphA3 expression in the PDAC TME supports tumour growth, we generated transgenic mice with doxycycline (Dox) inducible shRNA- mediated knockdown of EphA3 expression. Dox induction of shRNA is confirmed by a GFP reporter.  Our results indicate that in vivo knockdown of EphA3 results in reduced tumour growth in mice, indicating an important role of CAFs/MSCs recruited to tumours. Targeting EphA3 on cells, such as with antibody-based drugs, could be a therapeutic approach to inhibit pancreatic tumour growth.