Three-dimensional
tumor models accurately describe different aspects of the tumor microenvironment and are readily available for mechanistic studies of
tumor biology and for
drug screening. Nevertheless, these systems often overlook biomechanical stimulation, another fundamental driver of
tumor progression. To address this issue, we cultured
Ewing sarcoma (ES) cells on electrospun poly(ε-
caprolactone) 3D scaffolds within a flow perfusion
bioreactor. Flow-derived shear stress provided a physiologically relevant mechanical stimulation that significantly promoted
insulin-like growth factor-1 (IGF1) production and elicited a superadditive release in the presence of exogenous IGF1. This finding is particularly relevant, given the central role of the IGF1/
IGF-1 receptor (IGF-1R) pathway in ES
tumorigenesis and as a promising clinical target. Additionally, flow perfusion enhanced in a rate-dependent manner the sensitivity of ES cells to IGF-1R inhibitor
dalotuzumab (MK-0646) and showed shear stress-dependent resistance to the IGF-1R blockade. This study demonstrates shear stress-dependent ES cell sensitivity to
dalotuzumab, highlighting the importance of biomechanical stimulation on ES-acquired drug resistance to IGF-1R inhibition. Furthermore, flow perfusion increased nutrient supply throughout the scaffold, enriching ES culture over static conditions. Our use of a tissue-engineered model, rather than human
tumors or xenografts, enabled precise control of the forces experienced by ES cells, and therefore provided at least one explanation for the remarkable
antineoplastic effects observed by some ES
tumor patients from IGF-1R targeted
therapies, in contrast to the lackluster effect observed in cells grown in conventional monolayer culture.