Department of Biomedical Engineering, Columbia University, New York, NY 10025.
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032.
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2405257121. doi: 10.1073/pnas.2405257121. Epub 2024 Oct 7.
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 sites capable of recreating the physiologically relevant milieu of metastatic colonization may 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 for regulating tumor cell quiescence and proliferation in the three-dimensional eBM niche. We found that hematopoietic stem and progenitor cells (HSPCs) impacted TNBC cell growth and responded to cancer cell presence with a shift of HSPCs (CD34CD38) to downstream myeloid lineages (CD11bCD14). To account for tumor heterogeneity and show proof-of-concept ability for patient-specific studies, we demonstrate that 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 cell lines. We envision that this human tissue model will facilitate studies of niche-specific metastatic progression and individualized responses to treatment.
对转移疾病机制的不完全理解仍然阻碍着癌症的有效治疗。尽管在鉴定可用药靶方面取得了显著进展，但对于原发性肿瘤切除后缓解的患者，治疗选择仍然有限。能够重现转移性定植生理相关环境的转移性部位的生物工程化人体组织模型，可能会加强我们对癌症进展的理解，并有助于开发有效的治疗策略。我们报告了使用人骨髓（eBM）的工程化组织模型来识别调节癌细胞增殖的微环境线索，并研究三阴性乳腺癌（TNBC）细胞系如何影响造血。值得注意的是，骨髓龛的单个基质成分（成骨细胞、内皮细胞和间充质干细胞/基质细胞）对于调节肿瘤细胞在三维 eBM 龛中的静止和增殖都是至关重要的。我们发现造血干细胞和祖细胞（HSPCs）影响 TNBC 细胞的生长，并对癌细胞的存在做出反应，导致 HSPCs（CD34CD38）向下游髓系分化（CD11bCD14）的转变。为了解释肿瘤异质性并展示针对患者特异性研究的概念验证能力，我们证明了源自患者的肿瘤类器官在 eBM 中存活和增殖，导致髓系生成的明显转变，与观察到的侵袭性转移细胞系相似。我们设想这种人体组织模型将促进对龛特异性转移进展和针对个体的治疗反应的研究。
