Journal Article

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

Alborzinia, Hamed, Meierjohann, Svenja, Schmitz, Werner, Chen, Zhiyi, Espinet, Elisa, Fabiano, Marietta, Schweizer, Ulrich, Zheng, Jashuo, Schlicker, Lisa, Xavier da Silva, Thamara N, Varga, Julianna Patricia, Girardi, Enrico, Aroua, Nesrine, Przybylla, Adriana, Schulze, Almut, Superti‐Furga, Giulio, Flórez, Andrés F, Eilers, Martin, Michalke, Bernhard, Cheytan, Tasneem, Büchel, Gabriele, Freitas, Florencio Porto, dos Santos, Ancely Ferreira, Conrad, Marcus, Bartenhagen, Christoph, Zeisberger, Petra, Fischer, Matthias, Trumpp, Andreas, Batani, Jasmin, Friedmann Angeli, José Pedro, Haenlin, Julie, Yildiz, Umut, Vogel, Felix C E

2023

Overview

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 antiferroptotic 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. Synopsis The low‐density lipoprotein receptor (LRP8) was identified as a critical suppressor of ferroptosis in MYCN‐amplified neuroblastoma. Blocking selenium/selenocysteine uptake mechanisms via LRP8 offers a selective strategy to induce ferroptosis and disrupt GPX4 function. Ferroptosis, a cell death modality, is gaining interest as a therapeutic approach against challenging tumors. GPX4 is crucial for suppressing ferroptosis, but suitable in vivo inhibitors are lacking, limiting translation to cancer therapies. Genome‐wide and single‐cell CRISPR‐activation screens reveal LRP8 as a critical ferroptosis suppressor in MYCN‐amplified neuroblastoma. Blocking selenium/selenocysteine uptake via LRP8 disrupts GPX4 function and selectively induces ferroptotic cell death. LRP8 dependency emerges as the result of the low system Xc − activity suggesting that targeting LRP8 could be explore in other entities such as AML and lymphoma. Graphical Abstract The low‐density lipoprotein receptor (LRP8) was identified as a critical suppressor of ferroptosis in MYCN‐amplified neuroblastoma. Blocking selenium/selenocysteine uptake mechanisms via LRP8 offers a selective strategy to induce ferroptosis and disrupt GPX4 function.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Apoptosis / Cancer therapies / CRISPR / Datasets / EMBO03 / EMBO07 / EMBO27 / Ferroptosis / Genes / Genomes / Genotype & phenotype / Low density lipoprotein receptors / Metabolism / Neuroblastoma / Neuroblastoma cells / Proteins / Selenium / Selenocysteine / selenoprotein / synthetic lethality / Toxicity