Understanding and Mimicking Glioblastoma Cells Migration Strategies Through Hydrogel-Based 3D Models

Glioblastoma (GBM) is one of the most aggressive primary brain tumors in adults, characterized by rapid growth, diffuse infiltration of surrounding brain parenchyma, and resistance to conventional therapies, resulting in poor prognosis. The diffuse infiltrative behavior of GBM represents a major therapeutic challenge, as cancer cells can disseminate beyond identifiable margins of the tumor, escaping complete eradication and contributing to recurrence. GBM cell migration is a heterogeneous process that can occur through distinct strategies, including single-cell and collective patterns, as well as through the formation of multicellular structures known as “oncostreams”. Understanding the mechanisms underlying these migratory modalities may help identify new targets for limiting local tumor dissemination and disease progression. In this context, a variety of in vitro models have been developed to investigate these processes. Among these, hydrogel-based scaffolds represent a promising platform to recapitulate some selected biochemical and biophysical properties of the brain extracellular matrix, enabling the investigation of how the extracellular environment cues influence GBM cell migration and invasion. In this review, we discuss the major cellular strategies of GBM cell migration and tissue invasion and critically examine hydrogel-based in vitro models used to investigate these processes, highlighting their design principles, biological relevance, and current limitations.