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Published on: November 2, 2020
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.
Abstract:
The tumor microenvironment (TME) plays a pivotal role in breast cancer progression and metastasis, and the efficacy of targeted therapies is influenced by the heterogeneous nature of the TME. Interactions between breast cancer cells and their surrounding stromal cells modulate proliferation, invasion, and survival pathways, often via integrin-mediated mechanotransduction and growth factor signaling. Integrin-linked kinase (ILK) is a serine/threonine protein kinase that has been widely established as a critical driver of breast cancer progression, metastasis, and therapeutic resistance. Its expression is frequently upregulated in breast cancer tumors and correlates with poor prognosis. Given that ILK activity is highly dependent on cell-matrix interactions that are only recapitulated in 3D culture, we investigated the effect of an ILK inhibitor in 3D bioengineered compartmentalized breast tumoroid models to better mimic in vivo conditions. Two tumor cell masses (MDA-MB-231 or MCF-7) were cultured within a primary breast tissue stromal compartment representative of breast tissue or a metastatic representative of lung tissue. In highly invasive and highly hypoxic MDA-MB-231 3D tumoroid models, ILKI treatment was 2.2 fold more effective in 3D models representative of breast tissue (p-value < 0.0001) compared to those with the metastatic lung compartment (p-value = 0.03). However, ILKI treatment was slightly more effective (1.4 fold) in the less invasive and less hypoxic MCF-7 3D tumoroid models with the metastatic lung compartment compared to those with the primary breast compartment. Non-invasive imaging of oxygen gradients in the 3D models shows alleviation of hypoxia following treatment and correlation with enhanced treatment efficacy. These results emphasize the necessity of modeling both the tumor and the stroma since this interaction can directly influence drug efficacy. Moreover, ILK inhibitor treatment holds promise for breast cancer therapy particularly in chemotherapeutic resistant cases.
Insights
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.
