The tumor microenvironment plays a crucial role in shaping the tumor phenotype, yet replicating its complexity in vitro remains challenging. Traditional two-dimensional culture models lack physiologic relevance, and three-dimensional models often fail to fully capture native extracellular matrix (ECM) composition and cellular heterogeneity. In this issue of Cancer Research, Buckenmeyer and colleagues bridged this gap by integrating decellularized porcine-derived small intestinal submucosa ECM into monocellular spheroids, resulting in the formation of "MatriSpheres" with in vivo-like cancer cell heterogeneity. Although small intestinal submucosa ECM proved to be beneficial, several routes remain unexplored, such as incorporating other cell types (immune cells and cancer-associated fibroblasts) or species-, organ- or pathology-specific ECM or leveraging patient-derived tumor material. Pursuing these avenues of investigation to further develop Self-Matrix-Assembly to Recapitulate a Tumor (SMART) three-dimensional models could provide a powerful tool for cancer research, drug discovery, and personalized medicine. See related article by Buckenmeyer et al., p. 1577.
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