Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second most common cancer by 2030 in the UK. Prognosis is still woeful, despite surgical resection and/or current chemotherapeutic regimens. Several trials have been developed through the CRUK Precision-Panc initiative focussed on potentially actionable mutations (e.g. porcupine inhibitor for RNF43 mutants). However, the importance of transcriptional PDAC subtypes in therapeutic response is understudied to date. Our work identified the tumour subtypes in pancreatic cancer and the consensus is that there is a poor prognosis squamous/basal subtype. Subsequently we have found that this squamous subtype performs poorly at all stages of PDAC (both resectable and non-resectable). Our pre-clinical work has suggested that through targeting the microenvironment we can promote a subtype switch away from the squamous subtype. Whilst agents that target the tumour successfully promote recurrence with a switch to the squamous subtype.
PDACs exhibit significant microenvironmental heterogeneity and signalling from stroma to cancerous cells may influence tumour evolution and response to treatment. Our overarching aim is to characterize the tumour-stroma signalling networks that effect rapid PDAC progression and subtype evolution. Centre funding will be used to further develop our subtype-specific models of PDAC, characterise the complexity of human disease in both the tumour and the stroma, and facilitate a platform for therapeutic testing. We hypothesise that by integrating the mutational, transcriptional subtype, metabolic and spatial heterogeneity we may identify novel therapeutic opportunities for PDAC.
