The overall goal of the proposed research is to apply static and flow perfusion bioreactor culture of bone sarcoma cells, grown upon a tissue-engineered polymer/extracellular matrix (ECM) hybrid model that reliably mimics key features of the bone tumor niche, to advance our understanding of the IGF-1R/mTOR cancer- related pathway and its clinically-relevant resistance mechanisms. Our laboratory has reported in vivo-like IGF- 1R/mTOR expression patterns, closely related to those observed in human Ewing sarcoma tumors (ES), when established ES cell lines are grown upon innovative biologically inert 3D electrospun poly(?-caprolactone) (PCL) microfiber scaffolds rather than upon traditional plastic monolayers. The present proposal seeks to elucidate the precise mechanisms by which cell-cell and cell-ECM interactions stimulate an activated IGF- 1R/mTOR signaling state within this engineered 3D bone tumor microenvironment, as those interactions are critically important in initiating and maintaining ES. In parallel with determining the influence of those parameters under static cell culture, 3D scaffolds and culture conditions will be adapted to better emulate the native bone microenvironment: (a) varied flow perfusion rates will be used to assess the effect of shear stress upon cell retention while facilitating uniform distribution of Ewing cells within the scaffold, (b) PCL scaffolds will incorporate IGF-1 to mimic the high concentration of IGF-1 naturally released as tumors invade surrounding bone, (c) the effect of an osteogenic ECM upon the IGF-1R/mTOR signaling cascade will be determined using decellularized scaffolds upon which heterotypic mesenchymal stem cells, differentiated toward an osteoblastic lineage, are first grown, and (d) ES cells will be co-cultured with endothelial cells (EC) to determine how heterotypic cells interact within a fabricated 3D bone tumor model to elicit viable ES tumors. Finally, to determine the mechanism(s) by which Ewing sarcoma evades sensitivity to combined mTOR/IGF-1R targeted therapy, freshly-derived tumor specimens (obtained from Ewing sarcoma patients treated with Medi- 573/everolimus in an IRB-approved clinical trial), will be grown in primary culture within 3D scaffolds and compared to 2D culture and patient-derived tumor explants (PDTX) by proteomic analysis of the IGF- 1R/mTOR pathway and putative resistance mechanisms. This novel approach of studying Ewing sarcoma within an ex vivo preclinical model of the bone microenvironment presents tremendous potential for understanding chemotherapeutic efficacy and for determining resistance mechanisms to biologically targeted therapies.
The overall goal of the proposed research is to advance our understanding of cancer-related signaling pathways and their clinically-relevant resistance mechanisms by culturing human bone sarcoma cells within a tissue-engineered model that reliably mimics key features of the bone tumor microenvironment observed in patients. This project will focus specifically on Ewing sarcoma and the impact an engineered bone tumor niche has upon IGF-1R/mTOR signaling, a promising therapeutic target for Ewing sarcoma under active clinical investigation. The ability to accurately model resistance mechanisms within the described three-dimensional biomimetic tumor microenvironment is of immediate clinical value, allowing one to more effectively test novel treatment approaches.
|Puerto-Camacho, Pilar; Amaral, Ana Teresa; Lamhamedi-Cherradi, Salah-Eddine et al. (2018) Preclinical efficacy of endoglin-targeting antibody-drug conjugates for the treatment of Ewing sarcoma. Clin Cancer Res :|
|Chim, Letitia K; Mikos, Antonios G (2018) Biomechanical forces in tissue engineered tumor models. Curr Opin Biomed Eng 6:42-50|
|Smoak, Mollie M; Pearce, Hannah A; Mikos, Antonios G (2018) Microfluidic devices for disease modeling in muscle tissue. Biomaterials :|
|Subbiah, Vivek; Lamhamedi-Cherradi, Salah-Eddine; Cuglievan, Branko et al. (2018) Multimodality Treatment of Desmoplastic Small Round Cell Tumor: Chemotherapy and Complete Cytoreductive Surgery Improve Patient Survival. Clin Cancer Res 24:4865-4873|
|Santoro, Marco; Menegaz, Brian A; Lamhamedi-Cherradi, Salah-Eddine et al. (2017) Modeling Stroma-Induced Drug Resistance in a Tissue-Engineered Tumor Model of Ewing Sarcoma. Tissue Eng Part A 23:80-89|
|Trachtenberg, Jordan E; Placone, Jesse K; Smith, Brandon T et al. (2017) Extrusion-based 3D printing of poly(propylene fumarate) scaffolds with hydroxyapatite gradients. J Biomater Sci Polym Ed 28:532-554|
|Kesireddy, Venu; Kasper, F Kurtis (2016) Approaches for building bioactive elements into synthetic scaffolds for bone tissue engineering. J Mater Chem B 4:6773-6786|
|Santoro, Marco; Shah, Sarita R; Walker, Jennifer L et al. (2016) Poly(lactic acid) nanofibrous scaffolds for tissue engineering. Adv Drug Deliv Rev 107:206-212|
|Fong, Eliza L S; Wan, Xinhai; Yang, Jun et al. (2016) A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials 77:164-72|
|Chiu, Yu-Chieh; Fong, Eliza L; Grindel, Brian J et al. (2016) Sustained delivery of recombinant human bone morphogenetic protein-2 from perlecan domain I - functionalized electrospun poly (?-caprolactone) scaffolds for bone regeneration. J Exp Orthop 3:25|
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