Engineered ECM models: Opportunities to advance understanding of tumor heterogeneity

Intratumoral heterogeneity is a negative prognostic factor for cancer and commonly attributed to microenvironment-driven genetic mutations and/or the emergence of cancer stem-like cells. How aberrant extracellular matrix (ECM) remodeling regulates the phenotypic diversity of tumor cells, however, remains poorly understood due in part to a lack of model systems that allow isolating the physicochemical heterogeneity of malignancy-associated ECM for mechanistic studies. Here, we review the compositional, microarchitectural, and mechanical hallmarks of cancer-associated ECM and highlight biomaterials and engineering approaches to recapitulate these properties for in vitro and in vivo studies. Subsequently, we describe how such engineered platforms may be explored to define the spatiotemporal dynamics through which cancer-associated ECM remodeling regulates intratumoral heterogeneity and the cancer stem-like cell phenotype. Finally, we highlight future opportunities and technological advances to further elucidate the relationship between tumor-associated ECM dynamics and intratumoral heterogeneity.

Automated summary

Intratumoral heterogeneity is a negative prognostic factor for cancer, often caused by microenvironment-driven genetic mutations and alterations in cancer stem-like cells. Understanding how aberrant extracellular matrix (ECM) remodeling affects the phenotypic diversity of tumor cells is still limited, but biomaterials and engineering approaches offer opportunities to study this relationship in vitro and in vivo. Further research is needed to explore the spatiotemporal dynamics through which cancer-associated ECM remodeling influences intratumoral heterogeneity and the cancer stem-like cell phenotype.