3D Tissue-Engineered Tumor Model for Ewing's Sarcoma That Incorporates Bone-like ECM and Mineralization

Eric R. Molina, Letitia K. Chim, Maria C. Salazar, Gerry L. Koons, Brian A. Menegaz, Alejandra Ruiz-Velasco, Salah Eddine Lamhamedi-Cherradi, Amelia M. Vetter, Tejus Satish, Branko Cuglievan, Mollie M. Smoak, David W. Scott, Joseph A. Ludwig, Antonios G. Mikos

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)539-552
Number of pages14
JournalACS Biomaterials Science and Engineering
Volume6
Issue number1
DOIs
StatePublished - Jan 13 2020

Keywords

  • Ewing's sarcoma
  • bioengineered tumor microenvironment
  • bone tumor niche
  • cancer therapy resistance
  • insulin-like growth factor-1

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering

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