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Alborzinia, H.* ; Chen, Z.* ; Yildiz, U.* ; Freitas, F.P.* ; Vogel, F.C.E.* ; Varga, J.P.* ; Batani, J.* ; Bartenhagen, C.* ; Schmitz, W.* ; Büchel, G.* ; Michalke, B. ; Zheng, J. ; Meierjohann, S.* ; Girardi, E.* ; Espinet, E.* ; Flórez, A.F.* ; Dos Santos, A.F.* ; Aroua, N.* ; Cheytan, T.* ; Haenlin, J.* ; Schlicker, L.* ; Xavier da Silva, T.N.* ; Przybylla, A.* ; Zeisberger, P.* ; Superti-Furga, G.* ; Eilers, M.* ; Conrad, M. ; Fabiano, M.* ; Schweizer, U.* ; Fischer, M.* ; Schulze, A.* ; Trumpp, A.* ; Friedmann Angeli, J.P.*

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

EMBO Mol. Med. 15:e18014 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Ferroptosis ; Neuroblastoma ; Selenocysteine ; Selenoprotein ; Synthetic Lethality; Glutathione-peroxidase 4; Selenoprotein-p; Selenium Uptake; Ferroptosis; Gpx4; Inactivation; Dependency; Activation; Pathway

ISSN (print) / ISBN 1757-4676

e-ISSN 1757-4684

Journal EMBO Molecular Medicine

Quellenangaben Volume: 15, Issue: 8, Article Number: e18014

Publisher Wiley

Publishing Place Chichester

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Analytical BioGeoChemistry (BGC)
Institute of Metabolism and Cell Death (MCD)

Grants Deutsche Forschungsgemeinschaft (DFG)
European Research Council (ERC) under the European Union
Junior Group Leader program of the Rudolf Virchow Center, University of Wurzburg
SPP2306
CRC205
FOR2674
SFB873 - Deutsche Forschungsgemeinschaft
"RiskY-AML"
Junior Group Leader program of the Rudolf Virchow Center
"Integrate-TN" Consortium - Deutsche Krebshilfe
Dietmar Hopp Foundation
Humboldt Postdoctoral Fellowship
FOR2314
Foerderverein fur~krebskranke Kinder e.V. Koln
German Ministry of Science and Education (BMBF) as part of the e:Med initiative
Austrian Academy of Sciences
European Research Council
Marie Sklodowska-Curie fellowship
University of Wurzburg