Dynamic bioinspired coculture model for probing ER + breast cancer dormancy in the bone marrow niche

• Published in: Science advances Vol. 9; no. 10; p. eade3186
• Main Authors: Pradhan, Lina, Moore, DeVonte, Ovadia, Elisa M, Swedzinski, Samantha L, Cossette, Travis, Sikes, Robert A, van Golen, Kenneth, Kloxin, April M
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 10-03-2023
• Subjects: Applied Sciences and Engineering; Biomedicine and Life Sciences; Bone Marrow - pathology; Breast Neoplasms - metabolism; Cancer; Cell Communication; Coculture Techniques; Female; Humans; SciAdv r-articles; Signal Transduction; Tumor Microenvironment
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.ade3186

Late recurrences of breast cancer are hypothesized to arise from disseminated tumor cells (DTCs) that reactivate after dormancy and occur most frequently with estrogen receptor-positive (ER
) breast cancer cells (BCCs) in bone marrow (BM). Interactions between the BM niche and BCCs are thought to play a pivotal role in recurrence, and relevant model systems are needed for mechanistic insights and improved treatments. We examined dormant DTCs in vivo and observed DTCs near bone lining cells and exhibiting autophagy. To study underlying cell-cell interactions, we established a well-defined, bioinspired dynamic indirect coculture model of ER
BCCs with BM niche cells, human mesenchymal stem cells (hMSCs) and fetal osteoblasts (hFOBs). hMSCs promoted BCC growth, whereas hFOBs promoted dormancy and autophagy, regulated in part by tumor necrosis factor-α and monocyte chemoattractant protein 1 receptor signaling. This dormancy was reversible by dynamically changing the microenvironment or inhibiting autophagy, presenting further opportunities for mechanistic and targeting studies to prevent late recurrence.