The obtainment of innovative models recapitulating the complex tumor architecture and activity in vitro is a challenging drive in the understanding of pathology molecular bases, yet a crucial passage to the identification of targets for advanced oncotherapy. Topography tuning and gravitational unloading of cell culture can represent useful means in tumor biomimicry process: in this work, both were chosen for modelling of glioblastoma multiforme, a highly aggressive neoplasm that affects the central nervous system and that has poorly effective pharmacological and radiological countermeasures. Tumor modeling was pursued by the application of two-photon polymerization to fast prototyping of scaffolds suitable for U87-MG glioma cell culture, and by the exposure of cell-scaffold hybrids to simulated microgravity (s-µg) by rotation on random positioning machine. Glioma cell response was investigated by microscopy, quantitative reverse transcription-polymerase chain reaction and proteomic analyses, denoting synergic regulatory effects of cell scaffolding and s-µg on markers of tumor cell growth, metabolism and invasiveness.