The tumor microenvironment harbors essential components required for cancer progression including biochemical signals and mechanical cues. To study the effects of microenvironmental elements on Ewing's sarcoma (ES) pathogenesis, we tissue-engineered an acellular three-dimensional (3D) bone tumor niche from electrospun poly(ε-caprolactone) (PCL) scaffolds that incorporate bone-like architecture, extracellular matrix (ECM), and mineralization. PCL-ECM constructs were generated by decellularizing PCL scaffolds harboring cultures of osteogenic human mesenchymal stem cells. The PCL-ECM constructs simulated in vivo-like tumor architecture and increased the proliferation of ES cells compared to PCL scaffolds alone. Compared to monolayer controls, 3D environments facilitated the downregulation of the canonical insulin-like growth factor 1 receptor (IGF-1R) signal cascade through mechanistic target of rapamycin (mTOR), both of which are targets of recent clinical trials. In addition to the downregulation of canonical IGF-1R signaling, 3D environments promoted a reduction in the clathrin-dependent nuclear localization and transcriptional activity of IGF-1R. In vitro drug testing revealed that 3D environments generated cell phenotypes that were resistant to mTOR inhibition and chemotherapy. Our versatile PCL-ECM constructs allow for the investigation of the roles of various microenvironmental elements in ES tumor growth, cancer cell morphology, and induction of resistant cell phenotypes.
Keywords: Ewing’s sarcoma; bioengineered tumor microenvironment; bone tumor niche; cancer therapy resistance; insulin-like growth factor-1.