UMMS Affiliation

Program in Systems Biology; Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology

Publication Date

2018-08-06

Document Type

Article

Disciplines

Biochemistry | Cancer Biology | Cell Biology | Genetics and Genomics | Molecular Biology | Systems Biology

Abstract

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large-scale coculture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor-stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.

Keywords

Drug sensitivity, precision medicine, triple‐negative breast cancer, tumor microenvironment, tumor–stroma interaction

Rights and Permissions

© 2018 The Authors. Published under the terms of the CC BY 4.0 license.

DOI of Published Version

10.15252/msb.20188322

Source

Mol Syst Biol. 2018 Aug 6;14(8):e8322. doi: 10.15252/msb.20188322.

Journal/Book/Conference Title

Molecular systems biology

Related Resources

Link to Article in PubMed

PubMed ID

30082272

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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