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

Autor: Alborzinia H; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Chen Z; Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Yildiz U; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.; European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany., Freitas FP; Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Vogel FCE; Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg, Germany., Varga JP; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.; European Molecular Biology Organization, Heidelberg, Germany., Batani J; Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Bartenhagen C; Center for Molecular Medicine Cologne (CMMC) and Department of Experimental Pediatric Oncology, University Children's Hospital, Medical Faculty, University of Cologne, Cologne, Germany., Schmitz W; Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany., Büchel G; Mildred Scheel Early Career Center, University Hospital Würzburg, Würzburg, Germany., Michalke B; Research Unit Analytical BioGeoChemistry, Helmholtz Center München (HMGU), Neuherberg, Germany., Zheng J; Institute of Metabolism and Cell Death, Helmholtz Zentrum München (HMGU), Neuherberg, Germany., Meierjohann S; Department of Pathology, University of Würzburg, Würzburg, Germany., Girardi E; CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Solgate GmbH, Klosterneuburg, Austria., Espinet E; Anatomy Unit, Department of Pathology and Experimental Therapy, School of Medicine, University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain.; Molecular Mechanisms and Experimental Therapy in Oncology Program (Oncobell), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain., Flórez AF; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA., Dos Santos AF; Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany., Aroua N; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Cheytan T; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Haenlin J; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Schlicker L; Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg, Germany., Xavier da Silva TN; Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg, Germany., Przybylla A; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Zeisberger P; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Superti-Furga G; CeMM-Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria., Eilers M; Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany., Conrad M; Institute of Metabolism and Cell Death, Helmholtz Zentrum München (HMGU), Neuherberg, Germany., Fabiano M; Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany., Schweizer U; Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany., Fischer M; Center for Molecular Medicine Cologne (CMMC) and Department of Experimental Pediatric Oncology, University Children's Hospital, Medical Faculty, University of Cologne, Cologne, Germany., Schulze A; Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg, Germany., Trumpp A; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH), Heidelberg, Germany.; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Friedmann Angeli JP; Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2023 Aug 07; Vol. 15 (8), pp. e18014. Date of Electronic Publication: 2023 Jul 12.
DOI: 10.15252/emmm.202318014
Abstrakt: 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.
(© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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