The Revolutionary Roads to Study Cell–Cell Interactions in 3D In Vitro Pancreatic Cancer Models

SIMPLE SUMMARY: Pancreatic cancer is an extremely lethal malignancy with a survival rate lower than any other cancer type. For decades, two-dimensional (2D) cultures have been the cornerstone for studying cancer cell biology and drug testing, due to their simplicity and cost. However, their inability to reconstitute the tumor architecture, the absence of nutrient and oxygen supply gradients, as well as the lack of appropriate mechano-forces that mimic the extracellular microenvironment, make them an inadequate model to accurately reproduce tissue level-specific characteristics. Bioengineering systems, such as three-dimensional (3D) patient-specific models, are progressively emerging as systems better able to mimic the biology of pancreatic tumors and to test new anticancer therapies, as they more efficiently recapitulate the complex tumor microenvironment characteristic of pancreatic tumors. Here, we review how cellular component interactions, within the pancreatic tumor microenvironment, have been studied and mimicked in 3D cell culture models, and discuss selected emerging therapeutic strategies, addressing their limitations and future perspectives. ABSTRACT: Pancreatic cancer, the fourth most common cancer worldwide, shows a highly unsuccessful therapeutic response. In the last 10 years, neither important advancements nor new therapeutic strategies have significantly impacted patient survival, highlighting the need to pursue new avenues for drug development discovery and design. Advanced cellular models, resembling as much as possible the original in vivo tumor environment, may be more successful in predicting the efficacy of future anti-cancer candidates in clinical trials. In this review, we discuss novel bioengineered platforms for anticancer drug discovery in pancreatic cancer, from traditional two-dimensional models to innovative three-dimensional ones.