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.

Pancreatic cancer: from early detection to personalized treatment approaches

“…Nanoparticles have the potential to target tumour and stromal elements, improving imaging contrast 61 . Molecular imaging, coupled with conventional techniques, holds promise for early lesion identification 62 – 65 .…”

3D genomics and its applications in precision medicine

“…At present, there are many controversies about the concept of super-enhancers [ 117 ], but because it satisfies people’s needs for narrowing the research candidates, the research on super-enhancers has made explosive progress [ 118 , 119 ]. For example, in cancer research, super-enhancers are used as a new type of drug target [ 120 ]; in cell research, they are used as candidates for nuclear microenvironment research [ 121 ]; in immune cells, they are used as key factors in developmental regulation [ 122 , 123 ]. However, the specific composition, regulatory mechanism, and biological functions of super enhancers need to be further analyzed.…”

βIII-Tubulin is a Brake on Extrinsic Cell-Death in Pancreatic Cancer

“…In fact, the highly fibrotic stroma produced by cancer-associated fibroblasts (CAFs) can hinder drug delivery and together with pro-tumourigenic crosstalk between PDAC cells and CAFs promote the metastatic and chemoresistant nature of PDAC [7,8]. Novel therapeutic strategies should not simply target PDAC cells only but address the complex and heterogeneous multicellular microenvironment that characterises PDAC [6].…”

“…Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies with 5-year survival of <11% [1]. This is attributed to the disease being diagnosed at an advanced stage, with chemoresistance, metastases, and a complex multi-cellular microenvironment that can drive tumour progression [2][3][4][5][6]. In fact, the highly fibrotic stroma produced by cancer-associated fibroblasts (CAFs) can hinder drug delivery and together with pro-tumourigenic crosstalk between PDAC cells and CAFs promote the metastatic and chemoresistant nature of PDAC [7,8].…”