Hydrogel models of pancreatic adenocarcinoma to study cell mechanosensing.

Abstract

Pancreatic adenocarcinoma (PDAC) is the predominant form of pancreatic cancer and one of the leading causes of cancer-related death worldwide, with an extremely poor prognosis after diagnosis. High mortality from PDAC arises partly due to late diagnosis resulting from a lack of early-stage biomarkers and due to chemotherapeutic drug resistance, which arises from a highly fibrotic stromal response known as desmoplasia. Desmoplasia alters tissue mechanics, which triggers changes in cell mechanosensing and leads to dysregulated transcriptional activity and disease phenotypes. Hydrogels are effective in vitro models to mimic mechanical changes in tissue mechanics during PDAC progression and to study the influence of these changes on mechanosensitive cell responses. Despite the complex biophysical changes that occur within the PDAC microenvironment, carefully designed hydrogels can very closely recapitulate these properties during PDAC progression. Hydrogels are relatively inexpensive, highly reproducible and can be designed in a humanised manner to increase their relevance for human PDAC studies. In vivo models have some limitations, including species-species differences, high variability, expense and legal/ethical considerations, which make hydrogel models a promising alternative. Here, we comprehensively review recent advancements in hydrogel bioengineering for developing our fundamental understanding of mechanobiology in PDAC, which is critical for informing advanced therapeutics.