A patient-derived decellularized extracellular matrix hydrogel as a biomimetic scaffold for advanced 3D colorectal cancer modeling

Colorectal cancer (CRC) is among the most prevalent cancers globally and is associated with a high mortality rate, particularly in advanced stages. In the realm of drug discovery, the use of innovative and highly translational pre-clinical CRC models is essential. Currently, the most relevant in vitro tumor approaches are three dimensional (3D) models. However, most 3D models of solid tumors are based either on synthetic materials or animal-derived commercial hydrogels, which fail to accurately mimic the biology of native tissues and originate from non-human sources. In contrast, hydrogels derived from human decellularized extracellular matrix (ECM) retain signaling cues from native tissue and represent a bioactive mechanical structure that can foster tumor cell growth in a tissue-specific 3D in vitro environment. Here, we demonstrated that patient-derived decellularized colon ECM can be processed into a hydrogel, producing the CologEM. CologEM formulation process preserved key ECM proteins, such as collagens, glycosaminoglycans and secreted bioactive molecules belonging to the family of cytokine, chemokine, interleukin, growth factors and ECM-remodeling enzyme. CologEM displayed a fibrous ultrastructure with interconnected pores, with notable differences observed between 1 % and 3 % (w/v) CologEM. Both 1 % and 3 % CologEM showed good biocompatibility, with 3 % CologEM demonstrating a higher propensity to induce a mesenchymal phenotype and resistance to antitumor drugs. In conclusion, CologEM is a suitable scaffold for 3D CRC models as it replicates critical characteristics of the tumor microenvironment. This model holds promise for facilitating the discovery and development of chemotropic drugs for cancer treatment.