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Modeling Ovarian Cancer Multicellular Spheroid Behavior in a Dynamic 3D Peritoneal Microdevice
Published on: February 18, 2017
Multicompartmentalized Microvascularized Tumor-on-a-Chip to Study Tumor-Stroma Interactions and Drug Resistance in
Simona Plesselova1, Kristin Calar1, Hailey Axemaker1
1Present Address: Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD USA.
Introduction:
The majority of ovarian cancer (OC) patients receiving standard of care chemotherapy develop chemoresistance within 5 years. The tumor microenvironment (TME) is a dynamic and influential player in disease progression and therapeutic response. However, there is a lack of models that allow us to elucidate the compartmentalized nature of TME in a controllable, yet physiologically relevant manner and its critical role in modulating drug resistance.
Methods:
We developed a 3D microvascularized multiniche tumor-on-a-chip formed by five chambers (central cancer chamber, flanked by two lateral stromal chambers and two external circulation chambers) to recapitulate OC-TME compartmentalization and study its influence on drug resistance. Stromal chambers included endothelial cells alone or cocultured with normal fibroblasts or cancer-associated fibroblasts (CAF).
Results:
The tumor-on-a-chip recapitulated spatial TME compartmentalization including vessel-like structure, stromal-mediated extracellular matrix (ECM) remodeling, generation of oxygen gradients, and delayed drug diffusion/penetration from the circulation chamber towards the cancer chamber. The cancer chamber mimicked metastasis-like migration and increased drug resistance to carboplatin/paclitaxel treatment in the presence of CAF when compared to normal fibroblasts. CAF-mediated drug resistance was rescued by ECM targeted therapy. Critically, these results demonstrate that cellular crosstalk recreation and spatial organization through compartmentalization are essential to determining the effect of the compartmentalized OC-TME on drug resistance.
Conclusions:
Our results present a functionally characterized microvascularized multiniche tumor-on-a-chip able to recapitulate TME compartmentalization influencing drug resistance. This technology holds the potential to guide the design of more effective and targeted therapeutic strategies to overcome chemoresistance in OC.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s12195-024-00817-y.
Insights
A novel 3D tumor-on-a-chip model recreates the ovarian cancer tumor microenvironment (TME), revealing how cancer-associated fibroblasts promote chemoresistance. This technology can guide new ovarian cancer therapies.
Area of Science:
- Oncology
- Biomedical Engineering
- Drug Discovery
Background:
- Ovarian cancer (OC) frequently develops chemoresistance, limiting treatment efficacy.
- The tumor microenvironment (TME) significantly influences OC progression and therapeutic response.
- Existing models lack the complexity to fully represent TME compartmentalization and its role in drug resistance.
Purpose of the Study:
- To develop a 3D microvascularized multiniche tumor-on-a-chip model.
- To recapitulate ovarian cancer TME compartmentalization and study its impact on drug resistance.
- To investigate the role of cancer-associated fibroblasts (CAFs) in chemoresistance.
Main Methods:
- Constructed a five-chamber tumor-on-a-chip with a central cancer chamber and surrounding stromal and circulation chambers.
- Incorporated endothelial cells, normal fibroblasts, or CAFs into the stromal chambers.
- Analyzed TME features like vascularization, ECM remodeling, oxygen gradients, and drug penetration.
- Assessed carboplatin/paclitaxel resistance in the presence of different stromal components.
Main Results:
- The model successfully mimicked TME compartmentalization, including vessel-like structures and oxygen gradients.
- Cancer-associated fibroblasts (CAFs) significantly increased chemoresistance to carboplatin/paclitaxel.
- CAF-mediated drug resistance was linked to extracellular matrix (ECM) remodeling and could be reversed by ECM-targeted therapy.
- Demonstrated the critical role of cellular crosstalk and spatial organization in TME-mediated drug resistance.
Conclusions:
- The developed tumor-on-a-chip platform effectively models TME compartmentalization and its influence on ovarian cancer drug resistance.
- This technology provides a valuable tool for understanding chemoresistance mechanisms.
- It holds potential for designing targeted therapies to overcome chemoresistance in ovarian cancer.
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