title: Modeling Stroma-Induced Drug Resistance in a Tissue-Engineered Tumor Model of Ewing Sarcoma.
abstract: 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.
authors.affiliation: 1 Department of Chemical and Biomolecular Engineering, Rice University , Houston, Texas.|2 Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas.
authors.forename: Marco
authors.initials: M
authors.lastname: Santoro
authors.affiliation: 2 Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Menegaz
authors.affiliation: 2 Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas.
authors.forename: Salah-Eddine
authors.initials: SE
authors.lastname: Lamhamedi-Cherradi
authors.affiliation: 3 Department of Bioengineering, Rice University , Houston, Texas.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Molina
authors.affiliation: 4 Department of BioSciences, Rice University , Houston, Texas.
authors.forename: Danielle
authors.initials: D
authors.lastname: Wu
authors.affiliation: 5 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center , Houston, Texas.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.affiliation: 2 Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, Texas.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ludwig
authors.affiliation: 1 Department of Chemical and Biomolecular Engineering, Rice University , Houston, Texas.|3 Department of Bioengineering, Rice University , Houston, Texas.
authors.forename: Antonios G
authors.initials: AG
authors.lastname: Mikos
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins
keywords: Ewing sarcoma; drug resistance; flow perfusion bioreactor; tissue engineering; tumor model; tumor stroma