LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the anti-ferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc-. The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.

铁死亡（Ferroptosis）已成为癌症治疗中极具吸引力的治疗策略。阐明调控铁死亡的分子网络，或可揭示可被用于治疗获益的细胞脆弱位点。我们在铁死亡高敏感细胞中开展CRISPR激活筛选（CRISPR-activation screens），鉴定出硒蛋白P（SELENOP）受体LRP8是保护MYCN扩增型神经母细胞瘤细胞免受铁死亡侵袭的关键调控因子。LRP8的基因敲除会诱导铁死亡发生，其机制为硒半胱氨酸（selenocysteine）供给不足——而硒半胱氨酸是抗铁死亡硒蛋白GPX4翻译过程所必需的组分。这种依赖性源于Xc-系统等替代性硒摄取通路的低表达水平。在组成型及诱导型LRP8敲除原位异种移植瘤（orthotopic xenografts）模型中，我们验证了LRP8作为MYCN扩增型神经母细胞瘤细胞特异性易感靶点的结论。本研究揭示了一种此前未被阐明的选择性铁死亡诱导机制，该机制或可作为高危神经母细胞瘤及其他潜在MYCN扩增实体瘤的治疗策略加以开发应用。