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Cancer Engineering: In Vitro Approaches To Study Cell Plasticity Within the Tumor Microenvironment

Wednesday, September 13, 2017

2:00 PM-3:30 PM

BIOMED Special Seminar

Cancer Engineering: In Vitro Approaches To Study Cell Plasticity Within the Tumor Microenvironment

Aranzazu Villasante, PhD
Associate Research Scientist
Department of Biomedical Engineering
Columbia University

In the last six years, we have generated a set of tissue-engineered (TE) models of tumors displaying stemness properties and cell plasticity within the tumor microenvironment. Specifically, we focused on Ewing’s sarcoma, Neuroblastoma and Glioblastoma. With these models in hand, we learnt fundamental information about vasculogenic mimicry, drug resistance and importantly, the role of microenvironment in regulating tumor cell biology.

We first described a TE model of Ewing’s sarcoma (EWS) that mimics the native bone tumor niche. This innovative model allows not only cross-talk between cancer cells but also between crucial bone microenvironment components, namely osteoblasts, extracellular matrix secreted by cells and native mineralized extracellular matrix. By using this approach cancer cell lines induced the expression of focal adhesion and cancer related genes highly expressed in tumors, recovered the original hypoxic and glycolytic tumor phenotype, and displayed vasculogenic mimicry features. Then, we introduced osteoclasts in the bone niche to address the role of cancer cells in osteoclasts activation during osteolysis. We observed decreases in bone volume density, bone connectivity and organic bone matrix deposition. Interestingly, the TE model recapitulated the effects of the therapeutic reagent zoledronic acid observed in patients.

We also demonstrated the utility of TE models of cancer for studies of tumor exosomes. We found that composition and stiffness of the scaffold regulated the exosomes released by the cancer cells, by mechanisms involving tensional forces. This TE model recapitulated some of the characteristics of exosomes we can observe in EWS type 1 patients, such as size and EZH2 mRNA content. Alternatively, we cultured this TE model into a mechanical loading bioreactor for better mimicking biomechanical forces in bone tumors. Interestingly, we found that biomechanical stimuli modulated anticancer drug sensitivity.

Finally, we engineered a vascularized model of neuroblastoma (NB) to study the effects of isotretinoin on tumor vasculature and drug-resistance. The bioengineered model recapitulated the clinically observed vasculogenesis and vasculogenic mimicry, and contained subpopulations of stem-like NB cells expressing high levels of SOX2. Our results reveal some roles of SOX2 in drug resistance and tumor relapse, and suggest that SOX2 could be a therapeutic target in NB.

Aranzazu Villasante, PhD, is a cancer engineer expert on pediatric cancers (Ewing's sarcoma and Neuroblastoma). She believes that the only way to defeat cancer is by developing better preclinical models for testing drugs and drug combinations. Her research approach is based on the careful analysis of the features of human tumors through a medical perspective to engineering predictive in vitro models of cancer by combining molecular biology and bioengineering tools.

Contact Information

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