TY  - JOUR
AU  - Alborzinia, Hamed
AU  - Chen, Zhiyi
AU  - Yildiz, Umut
AU  - Freitas, Florencio Porto
AU  - Vogel, Felix Christian Eduard
AU  - Varga, Julianna Patricia
AU  - Batani, Jasmin
AU  - Bartenhagen, Christoph
AU  - Schmitz, Werner
AU  - Büchel, Gabriele
AU  - Michalke, Bernhard
AU  - Zheng, Jashuo
AU  - Meierjohann, Svenja
AU  - Girardi, Enrico
AU  - Espinet, Elisa
AU  - Flórez, Andrés F
AU  - Dos Santos, Ancely Ferreira
AU  - Aroua, Nesrine
AU  - Cheytan, Tasneem
AU  - Haenlin, Julie
AU  - Schlicker, Lisa
AU  - Xavier da Silva, Thamara N
AU  - Przybylla, Adriana
AU  - Zeisberger, Petra
AU  - Superti-Furga, Giulio
AU  - Eilers, Martin
AU  - Conrad, Marcus
AU  - Fabiano, Marietta
AU  - Schweizer, Ulrich
AU  - Fischer, Matthias
AU  - Schulze, Almut
AU  - Trumpp, Andreas
AU  - Friedmann Angeli, José Pedro
TI  - LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.
JO  - EMBO molecular medicine
VL  - 15
IS  - 8
SN  - 1757-4676
CY  - Heidelberg
PB  - EMBO Press
M1  - DKFZ-2023-01391
SP  - e18014
PY  - 2023
N1  - #EA:A010#LA:A010# / 2023 Aug 7;15(8):e18014
AB  - 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.
KW  - ferroptosis (Other)
KW  - neuroblastoma (Other)
KW  - selenocysteine (Other)
KW  - selenoprotein (Other)
KW  - synthetic lethality (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37435859
DO  - DOI:10.15252/emmm.202318014
UR  - https://inrepo02.dkfz.de/record/277470
ER  -