Using Organotypic Tissue Slices to Investigate the Microenvironment of Pancreatic Cancer: Pharmacotyping and Beyond

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all major cancers and, disappointingly, neither immune- nor stroma-directed therapies are found to improve upon the current standard of care. Among the most challenging aspects of PDAC biology which impede clinical success are the physiological features of the pancreatic cancer microenvironment (TME), including the presence of a highly fibrotic extracellular matrix marked by perineural invasion and an immunosuppressive milieu. Many current strategies for PDAC therapy are focused on altering these features to improve therapeutic efficacy. This review discusses the recent investigations using organotypic tumor slices as a model system to study cellular and extracellular interactions of the pancreatic TME. Future studies utilizing such models may provide new insights into the TME by identifying mechanisms of communication between multiple cell types and investigating novel therapeutic approaches for personalized cancer therapy. Organotypic tissue slices prepared from patient tumors are a semi-intact ex vivo preparation that recapitulates many aspects of the tumor microenvironment (TME). While connections to the vasculature and nervous system are severed, the integral functional elements of the tumor remain intact for many days during the slice culture. During this window of time, the slice platforms offer a suite of molecular, biomechanical and functional tools to investigate PDAC biology. In this review, we first briefly discuss the development of pancreatic tissue slices as a model system. Next, we touch upon using slices as an orthogonal approach to study the TME as compared to other established 3D models, such as organoids. Distinct from most other models, the pancreatic slices contain autologous immune and other stromal cells. Taking advantage of the existing immune cells within the slices, we will discuss the breakthrough studies which investigate the immune compartment in the pancreas slices. These studies will provide an important framework for future investigations seeking to exploit or reprogram the TME for cancer therapy.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among major cancers, and current therapies have had limited success. Understanding the complex tumor microenvironment (TME) of PDAC, including fibrotic matrix and immunosuppressive features, is crucial for developing effective treatments. Organotypic tumor slices from patient tumors provide a valuable model system to study TME interactions and potential therapeutic approaches for personalized cancer therapy.