3D Bioprinted Glioblastoma Multiforme Models: How the Extracellular Matrix Glycosignature Influences Drug Response

Aberrant glycosylation is widely recognized as a hallmark of different types of cancer, including Glioblastoma multiforme (GBM). Deregulation of specific glycans’ expression within the extracellular matrix (ECM) contributes indeed to the generation of the tumoral niche, playing a crucial role in disease progression, recurrence, and drug response. An in silico prioritization filter based on available GBM transcriptomic data allowed to identify ECM glycosignature that correlates with poor prognosis, thus guiding the rational design of a GBM 3D in vitro model. Following these instructions, a bioink composed of gelatin functionalized with α‐NeuNAc‐(2→3)‐β‐D‐Gal‐ and chondroitin sulfate was synthesized, and the ECM glycosignature effect on cancer cells drug response was investigated. Multiplex immunofluorescence analysis, combined with high‐resolution nano‐computed tomography (nanoCT), demonstrated that specific matrix glycosignatures trigger an alternative Galectin‐3 /Mucin‐1 (MUC1)/Mucin‐4 (MUC4) axis coupled with structural ECM remodeling to evade pharmacological cytotoxicity. The findings from this study offer valuable insights into the complex interplay between the ECM glycan cues and the drug response in GBM, paving the way to develop more predictive in vitro models for preclinical drug screening and to design glycan‐targeted therapeutic strategies.