Organotypic breast tumor model elucidates dynamic remodeling of tumor microenvironment

Fibroblasts are a critical component of tumor microenvironments and associate with cancer cells physically and biochemically during different stages of the disease. Existing cell culture models to study interactions between fibroblasts and cancer cells lack native tumor architecture or scalability....

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Bibliographic Details
Published inBiomaterials Vol. 238; p. 119853
Main Authors Singh, Sunil, Ray, Lucille A., Shahi Thakuri, Pradip, Tran, Sydnie, Konopka, Michael C., Luker, Gary D., Tavana, Hossein
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier Ltd 01.04.2020
Subjects
Breast
Breast cancer
Breast Neoplasms
Cell Line, Tumor
Contractility
Fibroblasts
Humans
Invasion
Neoplasm Invasiveness
Organotypic tumor model
Triple Negative Breast Neoplasms
Tumor Microenvironment
Organotypic tumor model
Breast cancer
Tumor microenvironment
Invasion
Contractility
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Summary:Fibroblasts are a critical component of tumor microenvironments and associate with cancer cells physically and biochemically during different stages of the disease. Existing cell culture models to study interactions between fibroblasts and cancer cells lack native tumor architecture or scalability. We developed a scalable organotypic model by robotically encapsulating a triple negative breast cancer (TNBC) cell spheroid within a natural extracellular matrix containing dispersed fibroblasts. We utilized an established CXCL12 – CXCR4 chemokine-receptor signaling in breast tumors to validate our model. Using imaging techniques and molecular analyses, we demonstrated that CXCL12-secreting fibroblasts have elevated activity of RhoA/ROCK/myosin light chain-2 pathway and rapidly and significantly contract collagen matrices. Signaling between TNBC cells and CXCL12-producing fibroblasts promoted matrix invasion of cancer cells by activating oncogenic mitogen-activated protein kinase signaling, whereas normal fibroblasts significantly diminished TNBC cell invasiveness. We demonstrated that disrupting CXCL12 – CXCR4 signaling using a molecular inhibitor significantly inhibited invasiveness of cancer cells, suggesting blocking of tumor-stromal interactions as a therapeutic strategy especially for cancers such as TNBC that lack targeted therapies. Our organotypic tumor model mimics native solid tumors, enables modular addition of different stromal cells and extracellular matrix proteins, and allows high throughput compound screening against tumor-stromal interactions to identify novel therapeutics.
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Authors’ Contributions
Credit Author Statement
SS conducted experiments and wrote manuscript. PST assisted in Western blotting. ST assisted in phase contrast imaging. LAR. and MCK assisted with confocal imaging. GDL helped with design of experiments and editing the manuscript. HT designed the experiments and helped with data analysis and writing the manuscript.
SS conducted experiments and wrote and edited the manuscript drafts. PST assisted in Western blotting and analysis. ST assisted in phase contrast imaging and image analysis. LAR and MCK assisted with confocal imaging. GDL helped with design of experiments and editing of the manuscript. HT acquired funding for the project, designed the experiments, supervised the project, and helped with data analysis and writing the manuscript.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2020.119853