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Updated: Sep 11, 2025
Establishing 3-Dimensional Spheroids from Patient-Derived Tumor Samples and Evaluating their Sensitivity to Drugs
Published on: December 16, 2022
Utility of Multicellular Spheroids for Investigating Mechanisms of Chemoresistance in Triple-Negative Breast Cancer
Keith N Ncube1, Iman van den Bout2, Clarissa Willers3,4
1Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria 0007, South Africa.
Abstract:
Chemoresistance is a major challenge in the treatment of triple-negative breast cancer (TNBC). Multicellular spheroids are an attractive platform for investigating chemoresistance in TNBC, as they replicate the cues of the tumour microenvironment in vivo. We conducted a comprehensive literature search to summarise the multifactorial and interlinked mechanisms driving chemoresistance in TNBC spheroids. These mechanisms include spatial heterogeneity, hypoxia, extracellular matrix remodelling, tumour-stroma crosstalk, drug efflux, apoptotic resistance, and cancer stem cell signalling. Strategies for overcoming chemoresistance in TNBC spheroids include nanocarrier systems to overcome spatial diffusion limitations, pathway inhibition, and targeting tumour-microenvironment interactions. Despite their advantages, some spheroid models face challenges such as low reproducibility, a lack of heterogeneity, variability in size and shape, limited vascularisation, and constraints in long-term culture. Advanced culturing platforms such as clinostat bioreactors allow for extended culture periods, enabling mature spheroid drug testing. Furthermore, advanced analytical techniques provide spatially resolved spheroid data. These multifactorial and interlinked mechanisms reflect the tumour microenvironment in vivo that spheroids recapitulate, rendering them valuable models for studying chemoresistance. The incorporation of stromal components and advanced analytical workflows will enhance the utility and translational relevance of spheroids as reliable preclinical models for drug discovery in TNBC.
Insights
Multicellular spheroids mimic the tumor microenvironment to reveal chemoresistance mechanisms in triple-negative breast cancer (TNBC). Advanced models and analysis enhance spheroid utility for preclinical drug discovery in TNBC.
Area of Science:
- Oncology
- Cancer Biology
- Drug Discovery
Background:
- Chemoresistance presents a significant hurdle in treating triple-negative breast cancer (TNBC).
- Multicellular spheroids offer a promising in vitro model by replicating the tumor microenvironment's cues.
- Understanding chemoresistance mechanisms in TNBC is crucial for developing effective therapies.
Purpose of the Study:
- To comprehensively review the multifactorial mechanisms of chemoresistance in TNBC spheroids.
- To identify strategies for overcoming chemoresistance within these spheroid models.
- To evaluate the advantages and limitations of spheroid models for TNBC research.
Main Methods:
- Comprehensive literature search on TNBC spheroid chemoresistance.
- Analysis of mechanisms including spatial heterogeneity, hypoxia, ECM remodeling, and drug efflux.
- Review of therapeutic strategies like nanocarriers and pathway inhibition.
Main Results:
- Key chemoresistance drivers identified: spatial heterogeneity, hypoxia, ECM remodeling, stroma crosstalk, drug efflux, apoptotic resistance, and CSC signaling.
- Strategies to overcome resistance include nanocarriers, pathway inhibition, and targeting tumor-microenvironment interactions.
- Spheroid models face challenges: reproducibility, heterogeneity, size/shape variability, vascularization, and long-term culture limitations.
Conclusions:
- Spheroids are valuable preclinical models for studying TNBC chemoresistance due to their recapitulation of the in vivo tumor microenvironment.
- Advanced culturing (clinostat bioreactors) and analytical techniques improve spheroid model utility and translational relevance.
- Incorporating stromal components and advanced workflows will enhance spheroid models for TNBC drug discovery.
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