Three-dimensional (3D)
tumor models are gaining
traction in the research community given their capacity to mimic aspects of the tumor microenvironment absent in monolayer systems. In particular, the ability to spatiotemporally control cell placement within ex vivo 3D systems has enabled the study of
tumor-stroma interactions. Furthermore, by regulating biomechanical stimuli, one can reveal how biophysical cues affect stromal cell phenotype and how their phenotype impacts
tumor drug sensitivity. Both
tumor architecture and shear force have profound effects on
Ewing sarcoma (ES) cell behavior and are known to elicit
ligand-mediated activation of the
insulin-like growth factor-1 receptor (IGF-1R), thereby mediating resistance of ES cells to IGF-1R inhibitors. Here, we demonstrate that these same biophysical cues-modeled by coculturing ES cells and mesenchymal stem cells (MSCs) in 3D scaffolds within a flow perfusion
bioreactor-activate
interleukin-6 and
transcription factor Stat3. Critically, an active Stat3 pathway drastically alters the equilibrium of IGF-1R-targeted
ligands (IGF-1) and antagonists (IGFBP-3) secreted by MSCs. To elucidate how this might promote ES
tumor growth under physiological shear-stress conditions, ES cells and MSCs were co-cultured by using a flow perfusion
bioreactor at varying ratios that simulate a wide range of native MSC abundance. Our results indicate that ES cells and MSCs stimulate each other's growth. Co-targeting IGF-1R and Stat3 enhanced
antineoplastic activity over monotherapy treatment. Although this discovery requires prospective clinical validation in patients, it reveals the power of employing a more physiological tissue-engineered 3D
tumor model to elucidate how
tumor cells co-opt stromal cells to acquire drug resistance.