Self-assembling PeptiGels as a platform to recapitulate the tumour microenvironment in pancreatic cancer

This paid-for advertorial by Manchester BioGel appeared in the DDW / ELRIG UK Drug Discovery 2021 supplement in DDW Volume 22, Issue 4 – Fall 2021 Communication of cells with their microenvironment is vital in understanding intracellular processes. Most matrices lack the mechanical and biochemical tuneability necessary to recreate the cancer microenvironment. Here we discuss how PeptiGels are able to overcome these limitations. The tumour microenvironment has a low extracellular pH, high substrate stiffness and elevated temperature, and plays a critical role in modulating cancer cell migration, metabolism, and malignancy. This highlights the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of tuneable biomaterials have been developed to mimic the rigidity of the tumour extracellular matrix, more complex systems that also include pH and temperature remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. PeptiGels are a family of self-assembled peptide hydrogels that offer tuneable mechanical properties (1-20 kPa) combined with high reproducibility and biocompatibility. This makes them good candidates to recapitulate the properties of the tumour microenvironment in 2D and 3D culture. They are based on β-sheet-forming peptides that self-assemble to form nanofibrous porous hydrogel structures that mimic the architecture of the native ECM. The system is designed to gelate in response to changes in ionic strength, such as the addition of cell culture media, offering ease of fabrication and 3D cell encapsulation. Here, PeptiGels were investigated as a cell culture matrix in a pancreatic cancer in vitro model. It was demonstrated that the culture parameters, including the substrate stiffness, extracellular pH and temperature, could be independently controlled. Furthermore, it was used as a cell culture substrate to assess the effect of stiffness, pH and temperature on Suit2 cells, a pancreatic cancer cell line. Interestingly, these microenvironmental factors were shown to regulate two critical transcription factors in cancer: yes-associated protein 1 (YAP) and hypoxia inducible factor (HIF-1A). These results illustrate the importance of considering multiple microenvironmental factors when designing cancer models, as different culture parameters can have synergistic or antagonistic effects on different aspects of cell behaviour. Using PeptiGels to simultaneously modulate biochemical and mechanical properties creates a unique range of applications in mechanobiology and cancer. Images represent immunofluorescent staining of Pancreatic Adenocarcinoma Suit-2 cell line cultured on gamma 2 (soft, healthy tissue mimicking) and alpha 2 (stiff, tumour mimicking) peptide gels with low (6.0) and normal (7.4) pH. Stiff and acidic (tumour mimicking peptide gels) induce a biomechanical response in Pancreatic Ductal Adenocarcinoma suit-2 cells resulting in an increased proliferation.