Journal Article

DKFZ-2023-01391

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.

Alborzinia, H. (First author)DKFZ* ; Chen, Z. ; Yildiz, U. (First author)DKFZ* ; Freitas, F. P. ; Vogel, F. C. E.DKFZ* ; Varga, J. P.DKFZ* ; 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.DKFZ* ; Cheytan, T.DKFZ* ; Haenlin, J.DKFZ* ; Schlicker, L.DKFZ* ; Xavier da Silva, T. N.DKFZ* ; Przybylla, A.DKFZ* ; Zeisberger, P.DKFZ* ; Superti-Furga, G. ; Eilers, M. ; Conrad, M. ; Fabiano, M. ; Schweizer, U. ; Fischer, M. ; Schulze, A.DKFZ* ; Trumpp, A. (Last author)DKFZ* ; Friedmann Angeli, J. P.

2023
EMBO Press Heidelberg

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Please use a persistent id in citations: doi:10.15252/emmm.202318014

Abstract: 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.

Keyword(s): ferroptosis ; neuroblastoma ; selenocysteine ; selenoprotein ; synthetic lethality

Note: #EA:A010#LA:A010# / 2023 Aug 7;15(8):e18014

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Contributing Institute(s):

1. A010 Stammzellen und Krebs (A010)
2. Metabolismus und Microenvironment (A410)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2023

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Database coverage:
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