c-Jun N-terminal Kinase (JNK) is a potent oncogene in numerous cancers, including breast and pancreatic cancer. Although JNK can promote metastasis, it is also vital for tumour suppression and apoptotic signalling. Our research into the roles of JNK in triple negative breast cancer has unveiled the mechanism underlying these pleiotropic functions to be distinct, subcellular pools of JNK activity. Specifically, JNK activity was predominantly localised to the nucleus in normal breast tissue, but significantly elevated in the cytoplasm of triple-negative tumours. This prompted us to investigate whether similar patterns of subcellular JNK activity are observed and potentially targetable in metastatic Pancreatic Ductal Adenocarcinoma.
Our analysis of the ICGC patient cohort demonstrated that cytoplasmic JNK activity was constitutively elevated in pancreatic cancer, similar to the levels observed within TNBC tumours. Using inducible subcellular JNK inhibitors we carried out functional assays which revealed that inhibiting JNK in either the nucleus or the cytoplasm inhibited the proliferation of cells growing within a three-dimensional, organotypic collagen matrix. This was further characterised in vivo using a subcutaneous xenograft model which showed that inhibition of both forms of subcellular JNK significantly extended survival and slowed tumour growth. These results were also recapitulated within an orthotopic model, in which metastasis to the liver along with incidence of ascites were significantly reduced when JNK was inhibited in either the nucleus or cytoplasm.
This data suggests that while the dual JNK network states found within breast tissue differ from those seen in pancreatic cancer, JNK remains attractive therapeutic target. To investigate this further we have carried out RNA sequencing on xenograft tumours to understand the relationship and possible translocation of JNK between the nucleus and cytoplasm in PDAC.