Self-Assembling Polypeptide Hydrogels as a Platform to Recapitulate the Tumor Microenvironment

SIMPLE SUMMARY: The tumor microenvironment is characterized by increased tissue stiffness, low (acidic) pH, and elevated temperature, all of which contribute to the development of cancer. Improving our in vitro models of cancer, therefore, requires the development of cell culture platforms that can mimic these microenvironmental properties. Here, we study a new biomaterial composed of short amino acid chains that self-assemble into a fibrous hydrogel network. This material enables simultaneous and independent tuning of substrate rigidity, extracellular pH, and temperature, allowing us to mimic both healthy tissues and the tumor microenvironment. We used this platform to study the effect of these conditions on pancreatic cancer cells and found that high substrate rigidity and low pH promote proliferation and survival of cancer cells and activate important signaling pathways associated with cancer progression. ABSTRACT: The tumor microenvironment plays a critical role in modulating cancer cell migration, metabolism, and malignancy, thus, highlighting the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of stiffness-tunable biomaterials, reviewed here, have been developed to mimic the rigidity of the tumor extracellular matrix, culture systems that can recapitulate the broader extracellular context of the tumor microenvironment (including pH and temperature) remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. Here, we investigate a self-assembled polypeptide network hydrogel as a cell culture platform and demonstrate that the culture parameters, including the substrate stiffness, extracellular pH and temperature, can be independently controlled. We then use this biomaterial as a cell culture substrate to assess the effect of stiffness, pH and temperature on Suit2 cells, a pancreatic cancer cell line, and demonstrate that these microenvironmental factors can regulate two critical transcription factors in cancer: yes-associated protein 1 (YAP) and hypoxia inducible factor (HIF-1A).