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Updated: May 24, 2026
Live Imaging of Drug Responses in the Tumor Microenvironment in Mouse Models of Breast Cancer
Published on: March 24, 2013
Fluorescence-based experimental model to evaluate the concomitant effect of drugs on the tumour microenvironment and
Karthik Ramasamy1, Hazera Khatun, Lee Macpherson
1Division of Cancer Studies, Department of Haematological Medicine, Kings College London, UK.
Abstract:
The response of the tumour microenvironment to anti-cancer drugs can influence treatment efficacy. Current drug-screening methodologies fail to distinguish and quantify simultaneously the concomitant effect of drugs on the tumour stroma and cancer cells. To overcome this limitation we have developed a fluorescence-based experimental model that employs mCherry-labelled stromal cells (e.g. bone marrow fibroblastic stromal cells) co-cultured in direct contact with enhanced green fluorescent protein-labelled tumour cell lines for accurate assessment of proliferation and viability in both cell compartments and adhesion of tumour cells. Additionally, we used fluorescence-based image analysis to determine morphological changes that correlate with cell function (e.g. morphology of the actin cytoskeleton and nuclearity of osteoclasts to predict their bone resorption activity). Using this platform we have revealed that dexamethasone induces HS5 fibroblast proliferation and contact with multiple myeloma cells via a process involving Src/c-Abl kinases. Osteoclasts also inhibited dexamethasone-induced apoptosis in myeloma cells while retaining their normal morphology and functionality in bone resorption. Myeloma resistance to dexamethasone mediated by HS5 cells and osteoclasts was reversed by treatment with the Src/c-Abl inhibitor dasatinib but not with bortezomib. This new experimental platform provides a more precise screening of new therapeutics for improved efficacy of tumour cell killing within the bone marrow microenvironment.
Insights
A new fluorescence model accurately assesses drug effects on tumor cells and their microenvironment. This approach identified dexamethasone resistance in myeloma cells, which was reversed by dasatinib, offering improved therapeutic screening.
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Pharmacology
Background:
- The tumor microenvironment significantly impacts anti-cancer drug efficacy.
- Current drug screening methods cannot simultaneously assess drug effects on both tumor and stromal cells.
- A need exists for advanced models to evaluate drug responses within the complex tumor microenvironment.
Purpose of the Study:
- To develop and validate a novel fluorescence-based experimental model for simultaneous assessment of drug effects on tumor cells and their microenvironment.
- To investigate the mechanisms of drug resistance in multiple myeloma within the bone marrow microenvironment.
- To evaluate the efficacy of targeted inhibitors in overcoming drug resistance.
Main Methods:
- Co-culture of mCherry-labeled stromal cells with GFP-labeled tumor cell lines.
- Fluorescence-based imaging and analysis to quantify cell proliferation, viability, and adhesion.
- Morphological analysis of cellular components (e.g., actin cytoskeleton, osteoclasts) to predict function.
- Pharmacological treatments with dexamethasone, dasatinib, and bortezomib.
Main Results:
- The developed model accurately assesses proliferation, viability, and adhesion in co-cultured cells.
- Dexamethasone treatment induced HS5 fibroblast proliferation and myeloma cell adhesion via Src/c-Abl kinases.
- Osteoclasts protected myeloma cells from dexamethasone-induced apoptosis while maintaining bone resorption activity.
- Myeloma resistance to dexamethasone was reversed by dasatinib but not bortezomib.
Conclusions:
- The novel fluorescence-based platform enables precise, simultaneous evaluation of drug effects on tumor cells and the microenvironment.
- Src/c-Abl kinases play a crucial role in mediating dexamethasone resistance in myeloma.
- Targeted inhibition of Src/c-Abl kinases presents a potential strategy to overcome drug resistance in bone marrow malignancies.
- This platform facilitates more accurate screening of therapeutics for enhanced anti-cancer efficacy in the bone marrow microenvironment.
