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Updated: Jun 24, 2025
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
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.
Insights
A novel 3D tumor-on-a-chip model recreates the ovarian cancer tumor microenvironment (TME) to study chemoresistance. Cancer-associated fibroblasts in the TME significantly increase drug resistance, highlighting the importance of TME compartmentalization in treatment failure.
Area of Science:
- Oncology
- Biotechnology
- Biomedical Engineering
Background:
- Ovarian cancer (OC) patients often develop chemoresistance within five years of standard chemotherapy.
- The tumor microenvironment (TME) significantly influences OC progression and therapeutic response.
- Existing models lack the ability to controllably and physiologically recapitulate TME compartmentalization for studying drug resistance.
Purpose of the Study:
- To develop and characterize a 3D microvascularized multiniche tumor-on-a-chip model.
- To investigate the role of TME compartmentalization in modulating chemoresistance in ovarian cancer.
- To elucidate the impact of cellular crosstalk and spatial organization on drug resistance.
Main Methods:
- Construction of a five-chambered 3D tumor-on-a-chip device.
- Incorporation of endothelial cells, normal fibroblasts, or cancer-associated fibroblasts (CAFs) in stromal chambers.
- Analysis of TME features like vessel-like structures, ECM remodeling, oxygen gradients, and drug diffusion.
- Assessment of drug resistance to carboplatin/paclitaxel in the presence of different stromal components.
Main Results:
- The tumor-on-a-chip successfully recapitulated TME compartmentalization, including spatial organization and delayed drug penetration.
- Cancer-associated fibroblasts (CAFs) significantly increased metastasis-like migration and chemoresistance compared to normal fibroblasts.
- Extracellular matrix (ECM)-targeted therapy demonstrated efficacy in rescuing CAF-mediated drug resistance.
- Cellular crosstalk and spatial compartmentalization within the TME are critical determinants of drug resistance.
Conclusions:
- A functional microvascularized multiniche tumor-on-a-chip model was developed to recapitulate TME compartmentalization and its influence on drug resistance.
- This model provides a platform for understanding chemoresistance mechanisms in ovarian cancer.
- The technology has the potential to inform the development of targeted therapies to overcome chemoresistance in ovarian cancer.
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