人诱导多能干细胞衍生的骨髓微环境鉴定出了白血病龛位介导的治疗抵抗的一种临床可操作的驱动因素。
hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia.
机构信息
Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Herschel Building Level 6, Brewery Lane, Newcastle upon Tyne, NE1 7RU UK; Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST UK.
Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Herschel Building Level 6, Brewery Lane, Newcastle upon Tyne, NE1 7RU UK.
出版信息
Cell Rep Med. 2022 Aug 16;3(8):100717. doi: 10.1016/j.xcrm.2022.100717.
Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies. We reveal that mesenchymal (iMSC) and vascular niche-like (iANG) hiPSC-derived cells support ex vivo proliferation of patient-derived leukemia cells, affect dormancy, and mediate treatment resistance. iMSCs protect dormant and cycling blasts against dexamethasone, while iANGs protect only dormant blasts. Leukemia proliferation and protection from dexamethasone-induced apoptosis is dependent on cancer-niche interactions mediated by CDH2. Consequently, we test CDH2 antagonist ADH-1 (previously in Phase I/II trials for solid tumors) in a very aggressive patient-derived xenograft leukemia mouse model. ADH-1 shows high in vivo efficacy; ADH-1/dexamethasone combination is superior to dexamethasone alone, with no ADH-1-conferred additional toxicity. These findings provide a proof-of-concept starting point to develop improved, potentially safer therapeutics targeting niche-mediated cancer dependencies in blood cancers.
白血病细胞重新编程其微环境以增强原始细胞的增殖并增强治疗抗性。临床上靶向这种龛依赖性治疗抗性的方法仍不清楚。我们开发了人类诱导多能干细胞（hiPSC）工程化龛，以揭示可靶向治疗的癌症龛依赖性。我们发现间充质（iMSC）和血管样龛（iANG）hiPSC 衍生细胞支持患者来源的白血病细胞的体外增殖，影响休眠并介导治疗抗性。iMSCs 保护休眠和循环原始细胞免受地塞米松的影响，而 iANGs 仅保护休眠原始细胞。白血病的增殖和免受地塞米松诱导的细胞凋亡的保护取决于由 CDH2 介导的癌症-龛相互作用。因此，我们在一种非常侵袭性的患者来源的异种移植白血病小鼠模型中测试了 CDH2 拮抗剂 ADH-1（先前在实体瘤的 I/II 期试验中进行了测试）。ADH-1 在体内具有很高的疗效；ADH-1/地塞米松联合用药优于单独使用地塞米松，且 ADH-1 没有带来额外的毒性。这些发现为开发针对血液癌中龛介导的癌症依赖性的改进的、潜在更安全的治疗方法提供了概念验证的起点。
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