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Direct Bioprinting of 3D Multicellular Breast Spheroids onto Endothelial Networks
Published on: November 2, 2020
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Unlocking the Therapeutic Potential of Integrin-Linked Kinase Inhibitors in Bioengineered 3D Breast Tumor Stroma
Salma T Rafik1,2, Anuja Upadhyay1, Alexander J MacRobert1
1UCL Centre for 3D Models of Health and Disease, UCL Division of Surgery and Interventional Science, Faculty of Medical Sciences, Charles Bell House, London, UK.
Summary
This study shows that targeting integrin-linked kinase (ILK) with an inhibitor is more effective in 3D breast cancer models that mimic the tumor microenvironment (TME). Modeling both tumor and stromal interactions is crucial for predicting drug efficacy in breast cancer therapy.
Area of Science:
- Oncology
- Biotechnology
- Cell Biology
Background:
- The tumor microenvironment (TME) significantly impacts breast cancer progression, metastasis, and treatment response.
- Integrin-linked kinase (ILK) is a key driver of breast cancer progression and therapeutic resistance, with elevated expression linked to poor prognosis.
- ILK activity is dependent on cell-matrix interactions, necessitating advanced models for accurate study.
Purpose of the Study:
- To investigate the efficacy of an ILK inhibitor in 3D bioengineered breast tumoroid models that better recapitulate in vivo conditions.
- To assess how interactions between tumor cells and stromal compartments influence the effectiveness of ILK inhibition.
- To evaluate the impact of ILK inhibition on hypoxia within the tumor microenvironment.
Main Methods:
- Development of 3D bioengineered compartmentalized breast tumoroid models using MDA-MB-231 (highly invasive) or MCF-7 (less invasive) breast cancer cells.
- Co-culture of tumor cells within stromal compartments representing primary breast tissue or metastatic lung tissue.
- Treatment with an ILK inhibitor (ILKI) and assessment of efficacy using non-invasive imaging of oxygen gradients and treatment response metrics.
Main Results:
- ILKI treatment showed significantly higher efficacy (2.2-fold) in highly invasive MDA-MB-231 tumoroids within the breast tissue compartment compared to the lung compartment.
- ILKI treatment was slightly more effective (1.4-fold) in less invasive MCF-7 tumoroids within the lung compartment compared to the breast compartment.
- ILKI treatment led to alleviation of hypoxia in the 3D models, correlating with enhanced therapeutic efficacy.
Conclusions:
- Modeling both tumor and stromal components within a 3D microenvironment is essential for accurately predicting drug efficacy in breast cancer.
- ILK inhibitor treatment demonstrates significant promise as a therapeutic strategy for breast cancer, particularly in cases of chemotherapeutic resistance.
- Understanding the interplay between tumor cells, stroma, and the microenvironment is critical for developing effective targeted therapies.
