Journal Article Review Epublish
PubMed: 40806629 DOI: 10.3390/ijms26157503
Utility of Multicellular Spheroids for Investigating Mechanisms of Chemoresistance in Triple-Negative Breast Cancer.
Int J Mol Sci 26(15)
Authors: Keith N Ncube, Iman van den Bout, Clarissa Willers, Chrisna Gouws, Werner Cordier
Affiliations
- Department of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria 0007, South Africa.
- Department of Physiology, Faculty of Health Sciences, University of Pretoria, Pretoria 0007, South Africa.
- Centre of Excellence for Pharmaceutical Sciences (Pharmacenâ„¢), Faculty of Health Sciences, North-West University, Potchefstroom 2531, South Africa.
- NWU Desmond Tutu School of Medicine, Faculty of Health Sciences, North-West University, Potchefstroom 2531, 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.
MeSH
Cells, Triple Negative Breast Neoplasms, Microscopy, Electron, Scanning Transmission, Breast Neoplasms, Pharmaceutical Preparations, Neoplasms, Spheroids, Cellular, Breast