A 4D-tunable hydrogel for the study of the impact of the tumor microenvironment on the development of colorectal cancer

Project Summary/Abstract The goal of this proposal is to develop a platform created from advanced biomaterials that enable novel investigations into the physiochemical roles of the tumor microenvironment (TME) on the origins of colorectal cancer. Colorectal cancer is a leading cause of cancer deaths in the U.S. and is increasing in incidence. Virtually all of these tumors arise from adenomas or polyps whose progression to cancer is driven by physical and chemical changes within the TME in concert with genetic mutations. Although much is known about the genetics of colon cancer, relatively little is understood about how the physicochemical properties of the surrounding TME matrix impact the process of cancer initiation. Current evidence does suggest that these TME alterations are critical to adenoma formation and progression to cancer. To advance our understanding of this process, an interdisciplinary group of internationally renowned investigators with expertise in materials science, bioengineering, optical platforms, intestinal stem cell biology and oncology has been assembled to create a 4D-tunable hydrogel to study how these TME alterations impact the development of colorectal cancer. Advanced light-activated hydrogels and their fabrication in forming an accurate model of the colonic architecture at the micron scale will be extensively optimized and characterized. The light activatable biomaterials with controllable physiochemical properties will then form a foundational component of a colon microphysiologic system (MPS). Human intestinal cells will reside on the new biomatrix scaffolding possessing photo-controlled stiffness in both space and time and supporting formation of chemical gradients. To take full advantage of the new biomaterials tool set, a customized light-sheet platform and imaging cassette compatible with application of gradients of growth factors and oxygen will be developed to support the living colonic tissue on this bioengineered scaffold. The platform will enable high-quality imaging of large numbers of colonic crypts to generate data sets of sufficient size for statistical comparisons and hypothesis testing. This humanized, architecturally and physiochemically accurate biomaterials platform will then be used to reveal key characteristics of the TME’s influence on the hallmarks of cancer demonstrating the utility of these advanced biomaterials in studies of colon and other cancer types.