Understanding ER+ Breast Cancer Dormancy Using Bioinspired Synthetic Matrices for Long-Term 3D Culture and Insights
Elisa M Ovadia1, Lina Pradhan1, Lisa A Sawicki1
1Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, 19716, USA.
Advanced Biosystems
|July 1, 2020
Summary
Late breast cancer recurrences may stem from dormant cells. A new 3D model shows matrix properties influence estrogen-receptor positive (ER+) cell dormancy, unlike aggressive triple-negative cells.
Area of Science:
- Oncology
- Biomaterials Science
- Cell Biology
Background:
- Late recurrences of breast cancer, particularly estrogen-receptor positive (ER+) tumors, are linked to dormant disseminated tumor cells reactivating after years.
- Understanding the microenvironment's role in regulating tumor cell dormancy is crucial for preventing late recurrences.
- Existing human model systems are insufficient for studying these complex cell-microenvironment interactions.
Purpose of the Study:
- To establish and utilize a bioinspired 3D culture model to investigate how matrix properties at common recurrence sites affect ER+ breast cancer cell dormancy.
- To compare the dormancy behavior of ER+ cells with triple-negative breast cancer cells in response to varying matrix compositions.
- To identify molecular mechanisms, including gene expression and survival pathways, associated with dormancy in ER+ breast cancer cells.
Main Methods:
- Development of a robust, bioinspired 3D culture system using ER+ breast cancer cell lines (T47D, BT474).
- Culturing cells within matrices mimicking common sites of late recurrence to observe micrometastasis formation and dormancy.
- Employing bioinformatic analyses to assess gene expression signatures, including a "dormancy score," and pathways like autophagy.
Main Results:
- The 3D model successfully recapitulated micrometastasis formation and dormancy in ER+ cells, with timing dependent on matrix composition and cell type.
- Triple-negative breast cancer cells (MDA-MB-231) did not exhibit long-term dormancy in this model, consistent with their association with early recurrence.
- Bioinformatic analysis revealed an elevated "dormancy score" in ER+ cells and differential gene expression based on matrix properties, suggesting a link between dormancy and autophagy.
Conclusions:
- A novel 3D ER+ breast cancer cell dormancy model provides a platform for studying microenvironment interactions critical for late recurrence.
- Matrix properties significantly influence the balance between dormancy and growth in ER+ breast cancer cells.
- The findings highlight autophagy as a potential survival mechanism during dormancy and offer avenues for therapeutic strategies against late breast cancer recurrence.
