An engineered model of metastatic colonization of human bone marrow reveals breast cancer cell remodeling of the hematopoietic niche

• 成果类型: Article
• 署名作者: Baldassarri, Ilaria; Tavakol, Daniel Naveed; Graney, Pamela L.; Chramiec, Alan G.; Hibshoosh, Hanina; Vunjak-Novakovic, Gordana
• 署名单位: Columbia University; Columbia University; Columbia University; Columbia University; Columbia University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13003
• DOI: 10.1073/pnas.2405257121
• 发表日期: 2024-10-15
• 关键词: on-a-chip; mechanisms; dormancy; organoids; emergency

摘要

Incomplete understanding of metastatic disease mechanisms continues to hinder effective treatment of cancer. Despite remarkable advancements toward the identification of druggable targets, treatment options for patients in remission following primary tumor resection remain limited. Bioengineered human tissue models of metastatic capable of recreating the physiologically relevant milieu of metastatic colonization strengthen our grasp of cancer progression and contribute to the development of effective therapeutic strategies. We report the use of an engineered tissue model of human bone marrow (eBM) to identify microenvironmental cues regulating cancer cell proliferation and to investigate how triple- negative breast cancer (TNBC) cell lines influence hematopoiesis. Notably, individual stromal components of the bone marrow niche (osteoblasts, endothelial cells, and mesenchymal stem/stromal cells) were each critical regulating tumor cell quiescence and proliferation in the three- dimensional eBM niche. We found that hematopoietic stem and progenitor cells (HSPCs) impacted TNBC growth and responded to cancer cell presence with a shift of HSPCs (CD34+CD38-) to downstream myeloid lineages (CD11b+CD14+). To account for tumor heterogeneity and show proof- of- concept ability for patient- specific studies, we demonstrate patient- derived tumor organoids survive and proliferate in the eBM, resulting in distinct shifts in myelopoiesis that are similar to those observed for aggressively metastatic lines. We envision that this human tissue model will facilitate studies of niche- specific metastatic progression and individualized responses to treatment.