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

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.

Keywords: microenvironment; pancreatic cancer; pre-clinical models; precision medicine.

Figure 1

The tumour microenvironment is a key player in promoting chemoresistance in pancreatic ductal adenocarcinoma (PDAC). PDAC chemoresistance can be influenced by a broad range of factors in the tumour microenvironment. Cancer-associated fibroblasts (CAFs) secrete factors such as leukaemia inhibitory factor (LIF) and deoxycytidine which directly promote drug resistance and can also metabolise and inactivate drugs such as gemcitabine. Extracellular vesicles (EVs) and tumour associated macrophages (TAMs) can also secrete different factors to drive chemoresistance in PDAC cells. The extracellular matrix (ECM) can be a physical barrier to drug delivery by compressing blood vessels, and proteins that make up the ECM such as collagen, laminin and hyaluronan can activate survival pathways in PDAC cells to increase chemoresistance. Abbreviations: CAFs: Cancer-associated fibroblasts; ECM: Extracellular matrix; EVs: Extracellular vesicles; LIF: Leukaemia inhibitory factor; PDAC: Pancreatic ductal adenocarcinoma; ROS: Reactive oxygen species; TAMs: Tumour-associated macrophages.

Figure 2

Pre-clinical models to inform functional precision medicine in pancreatic ductal adenocarcinoma. Patient-derived pre-clinical models are needed to inform functional precision medicine. Importantly, each model has its strengths and limitations, and these need to be addressed when choosing models to guide precision medicine.

Figure 3

A proposed personalised medicine pipeline for patients with surgically resectable pancreatic ductal adenocarcinoma. If diagnostic biopsy is performed prior to surgery, organoids can be established to allow molecular profiling and drug screens to be performed. Then tumour explant/slice culture can be established from tissue obtained during surgery, which could allow any hits identified from the organoid molecular profiling or drug screen to be validated. Ex vivo explant/slice culture can also be used to test standard of care chemotherapy which can be particularly useful when no matched therapies are identified. These results can then be presented to a tumour board to guide personalised adjuvant treatment.