Transition to invasion in breast cancer: a microfluidic in vitro model enables examination of spatial and temporal effects
Open accessAbstract
The transition of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is a critical step in breast cancer progression. We introduce a simple microfluidic 3D compartmentalized system in which mammary epithelial cells (MCF-DCIS) are co-cultured with human mammary fibroblasts (HMFs), which promotes a transition from DCIS to IDC in vitro. The model enables control of both spatial (distance-dependence) and temporal (transition from larger clusters) aspects within the microenvironment, allowing recapitulation of the in vivo environment in ways not practical with existing experimental models. When HMFs were cultured some distance (0.5-1.5 mm) from the MCF-DCIS cells, we observed an initial morphological change, suggesting soluble factors can begin the transition. However, cell-cell contact with HMFs allowed the MCF-DCIS cells to complete the transition to invasion. Uniquely, the compartmentalized platform enables the analysis of the intrinsic second harmonic generation signal of collagen, providing a label-free quantitative analysis of DCIS-associated collagen remodeling. The arrayed microchannel-based model is compatible with existing infrastructure and, for the first time, provides a cost effective approach to test for inhibitors of pathways involved in DCIS progression to IDC allowing a screening approach to the identification of potential therapeutic targets. Importantly, the model can be easily adapted and generalized to a variety of cell-cell signaling studies.
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HMFs and MCF10-DCIS cells established a crosstalk at the interface between cancerous and normal microtissue sections.
“The HMFs and MCF10-DCIS cells established a crosstalk at the interface between the cancerous and normal microtissue sections.”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
MCF10-DCIS cancer cells adopted different shapes as a function of their distance from the interface.
“MCF10-DCIS cancer cells adopted different shapes (i.e., their circularity, roundness, and aspect ratio significantly changed) as a function of their distance from the interface”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
The change in shape of MCF10-DCIS cells and their ability to remodel the matrix suggested the onset of a DCIS to IDC transition.
“The change in shape of MCF710-DCIS cells, and their ability to remodel the matrix, suggested the onset of a DCIS to IDS transition.”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
Cell-cell contact between HMFs and MCF-DCIS cells favored the completed transition to an invasive phenotype.
“and the cell–cell contact between HMFs and MCF-DCIS cells favored the completed transition to an invasive phenotype.”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
Clusters of cells in co-culture (HMF and MCF10-DCIS) affected the structure of the matrix significantly more than did monocultured MCF10-DCIS cells.
“Clusters of cells in co-culture (HMF and MCF10-DCIS) affected the structure (physical appearance under the microscope) of the matrix significantly more than did monocultured MCF10-DCIS cells.”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
The DCIS to IDC transition strongly depended on the distance between the cells, being more evident around the cell interfaces.
“This transition strongly depended on the distance between the cells, being more evident around the cell interfaces.”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
Sung's experimental results suggested an underlying two-step molecular mechanism for the transition from DCIS to IDC.
“Sung’s experimental results suggested an underlying two-step molecular mechanism for the transition from DCIS to IDS”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
Soluble factors could initiate the DCIS to IDC transition.
“suggesting that soluble factors could initiate the transition”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
An initial morphological change was observed when HMFs were cultured at 0.5-1.5 mm from MCF-DCIS cells.
“An initial morphological change was first observed when HMFs were cultured at some distance (0.5–1.5 mm) from the MCF-DCIS cells”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [33]
Sung's group proposed a 3D microfluidic model of breast cancer invasion using surface tension pumping to achieve the sequential loading of cells at different time points.
“Based on spheroids, Sung’s group proposed a 3D microfluidic model of breast cancer invasion using surface tension pumping to achieve the sequential loading of cells at different time points177.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [177]
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- Authors
- Sung, K. E., Yang, N., Pehlke, C., Keely, P. J., Eliceiri, K. W., Friedl, A., & Beebe, D. J.
- Affiliations
- University of Wisconsin–Madison (US)
- United States Department of Veterans Affairs (US)
- Corresponding author
- Beebe, David J.
- Venue
- Integr. Biol.
- Publisher
- Oxford University Press (OUP)
- Published
- 2011
- Volume
- 3
- Issue
- 4
- Pages
- 439-450
- ISSN
- 1757-9694 (ISSN-L)
- 1757-9708
- PMC
- PMC3094750
- OpenAlex
- W2103232525
- Cited by
- 226
- References
- 32
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 4 · 2023: 8 · 2022: 14 · 2021: 19 · 2020: 22 · 2019: 12 · 2018: 20 · 2017: 22 · 2016: 15 · 2015: 19 · 2014: 18 · 2013: 23 · 2012: 16
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Integrative Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA107012, R01CA114462, R33CA137673, K25CA104162)
- U.S. National Library of Medicine (T15LM007359)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- ductal carcinoma in situ, invasive ductal carcinoma, breast cancer progression, mammary epithelial cells, cell-cell contact, collagen remodeling, second harmonic generation microscopy, microchannel arrays, therapeutic target screening, tumor microenvironment
- MeSH terms
- Actins, Animals, Breast Neoplasms, Cell Line, Collagen, Drug Combinations, Female, Fibroblasts, Humans, Laminin, Mice, Nude, Neoplasm Invasiveness, Proteoglycans, Time Factors, Cadherins, Extracellular Matrix Proteins, Coculture Techniques, Fibrillar Collagens, Collagen Type I, Collagen Type IV, Microscopy, Fluorescence, Multiphoton, Carcinoma, Ductal, Cell Line, Tumor, Microfluidic Analytical Techniques, Cell Proliferation, Mice
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