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Utilizing a dynamic well-defined 3D co-culture model for investigations in ER+ breast cancer dormancy
Date
2022
Authors
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Publisher
University of Delaware
Abstract
Prevention of late breast cancer recurrences remains a clinical challenge for physicians. Detection of dormant cancer cells, which are often few in number, is challenging within current diagnostic limitations. Further, current systemic therapies, including neoadjuvant and adjuvant therapies, given to patients before and/or after surgery to eliminate residual cancer cells, are limited by lack of specificity towards these non-proliferating cells. Limited molecular insights into underlying dormancy and reactivation continues to define a gap within our knowledge that remains as to how these breast cancer cells are able to survive through dormancy and reactivation. It has been hypothesized and a few insights have shown that there are key cell-cell and cell-extracellular matrix (ECM) interactions between disseminated ER+ cancer cells and the bone microenvironment that contribute to late recurrence, inducing dormancy in breast cancer cells (BCCs) initially with metastatic outbreak at later times. My thesis aimed to utilize a recently-established, well-defined three-dimensional (3D) ER+ breast cancer dormancy and reactivation co-culture model and innovative molecular tools to understand and target the molecular regulators of ER+ breast cancer dormancy. In collaboration with colleagues, I contributed to studies that identified TNFα and MCP1 as soluble factor regulators of ER+ cancer dormancy induction. Additionally, T47D ER+ breast cancer cells were engineered toward reporting dormancy in real-time using lentivirus with opportunities for single-cell assessment of ER+ breast cancer dormancy in live cells. Continued development of reporter strategies established here will be useful in the assessment of the effects of known small molecule anti-cancer therapeutics. I also was able to isolate and identify extracellular vesicles from this dormancy culture system, which could prove useful in future studies for dormancy induction. These insights and tools provide the framework for more detailed identification and targeting of dormancy and reactivation related biochemical factors and pathways.
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Keywords
Breast cancer, Dormancy, Cell-extracellular matrix, Osteoblast, Dormancy induction