Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer?

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all major cancers. We now know that a ‘one-size-fits-all’ approach when treating PDAC patients does not work, so research has focused on developing personalised treatment strategies based on the biology of each patient’s tumour. However, most of these strategies ignore the presence of the characteristic fibrotic PDAC stroma which can act like a fortress to protect the tumour from chemotherapy and drive its aggressive nature. In this review, we summarise the role of this ‘fortress’ in protecting PDAC from chemotherapy and highlight the need for pre-clinical models that are informing precision medicine to reflect this hallmark feature of PDAC. We also propose the power of ex vivo whole-tissue culture models that mimic the tumour and its surrounding fortress to inform personalised treatment for PDAC. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and no significant improvement in patient survival has been seen in the past three decades. Treatment options are limited and selection of chemotherapy in the clinic is usually based on the performance status of a patient rather than the biology of their disease. In recent years, research has attempted to unlock a personalised treatment strategy by identifying actionable molecular targets in tumour cells or using preclinical models to predict the effectiveness of chemotherapy. However, these approaches rely on the biology of PDAC tumour cells only and ignore the importance of the microenvironment and fibrotic stroma. In this review, we highlight the importance of the microenvironment in driving the chemoresistant nature of PDAC and the need for preclinical models to mimic the complex multi-cellular microenvironment of PDAC in the precision medicine pipeline. We discuss the potential for ex vivo whole-tissue culture models to inform precision medicine and their role in developing novel therapeutic strategies that hit both tumour and stromal compartments in PDAC. Thus, we highlight the critical role of the tumour microenvironment that needs to be addressed before a precision medicine program for PDAC can be implemented.