LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma
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 th...
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Springer Nature
2023-07-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202318014 |
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| author | Hamed Alborzinia Zhiyi Chen Umut Yildiz Florencio Porto Freitas Felix C E Vogel Julianna Patricia Varga Jasmin Batani Christoph Bartenhagen Werner Schmitz Gabriele Büchel Bernhard Michalke Jashuo Zheng Svenja Meierjohann Enrico Girardi Elisa Espinet Andrés F Flórez Ancely Ferreira dos Santos Nesrine Aroua Tasneem Cheytan Julie Haenlin Lisa Schlicker Thamara N Xavier da Silva Adriana Przybylla Petra Zeisberger Giulio Superti‐Furga Martin Eilers Marcus Conrad Marietta Fabiano Ulrich Schweizer Matthias Fischer Almut Schulze Andreas Trumpp José Pedro Friedmann Angeli |
| author_facet | Hamed Alborzinia Zhiyi Chen Umut Yildiz Florencio Porto Freitas Felix C E Vogel Julianna Patricia Varga Jasmin Batani Christoph Bartenhagen Werner Schmitz Gabriele Büchel Bernhard Michalke Jashuo Zheng Svenja Meierjohann Enrico Girardi Elisa Espinet Andrés F Flórez Ancely Ferreira dos Santos Nesrine Aroua Tasneem Cheytan Julie Haenlin Lisa Schlicker Thamara N Xavier da Silva Adriana Przybylla Petra Zeisberger Giulio Superti‐Furga Martin Eilers Marcus Conrad Marietta Fabiano Ulrich Schweizer Matthias Fischer Almut Schulze Andreas Trumpp José Pedro Friedmann Angeli |
| author_sort | Hamed Alborzinia |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f738f088a5b24d4d84df76ffa09916f9 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-07-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-f738f088a5b24d4d84df76ffa09916f92025-08-20T03:43:20ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-07-0115811710.15252/emmm.202318014LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastomaHamed Alborzinia0Zhiyi Chen1Umut Yildiz2Florencio Porto Freitas3Felix C E Vogel4Julianna Patricia Varga5Jasmin Batani6Christoph Bartenhagen7Werner Schmitz8Gabriele Büchel9Bernhard Michalke10Jashuo Zheng11Svenja Meierjohann12Enrico Girardi13Elisa Espinet14Andrés F Flórez15Ancely Ferreira dos Santos16Nesrine Aroua17Tasneem Cheytan18Julie Haenlin19Lisa Schlicker20Thamara N Xavier da Silva21Adriana Przybylla22Petra Zeisberger23Giulio Superti‐Furga24Martin Eilers25Marcus Conrad26Marietta Fabiano27Ulrich Schweizer28Matthias Fischer29Almut Schulze30Andreas Trumpp31José Pedro Friedmann Angeli32Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of WürzburgHeidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of WürzburgDivision of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of WürzburgCenter for Molecular Medicine Cologne (CMMC) and Department of Experimental Pediatric Oncology, University Children's Hospital, Medical Faculty, University of CologneDepartment of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of WürzburgMildred Scheel Early Career Center, University Hospital WürzburgResearch Unit Analytical BioGeoChemistry, Helmholtz Center München (HMGU)Institute of Metabolism and Cell Death, Helmholtz Zentrum München (HMGU)Department of Pathology, University of WürzburgCeMM‐Research Center for Molecular Medicine of the Austrian Academy of SciencesAnatomy Unit, Department of Pathology and Experimental Therapy, School of Medicine, University of Barcelona (UB), L'Hospitalet de LlobregatDepartment of Molecular and Cellular Biology, Harvard UniversityRudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of WürzburgHeidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ)Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)CeMM‐Research Center for Molecular Medicine of the Austrian Academy of SciencesDepartment of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, University of WürzburgInstitute of Metabolism and Cell Death, Helmholtz Zentrum München (HMGU)Institut für Biochemie und Molekularbiologie, Rheinische Friedrich‐Wilhelms‐Universität BonnInstitut für Biochemie und Molekularbiologie, Rheinische Friedrich‐Wilhelms‐Universität BonnCenter for Molecular Medicine Cologne (CMMC) and Department of Experimental Pediatric Oncology, University Children's Hospital, Medical Faculty, University of CologneDivision of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ)Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH)Rudolf Virchow Zentrum (RVZ), Center for Integrative and Translational Bioimaging, University of WürzburgAbstract 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.https://doi.org/10.15252/emmm.202318014ferroptosisneuroblastomaselenocysteineselenoproteinsynthetic lethality |
| spellingShingle | Hamed Alborzinia Zhiyi Chen Umut Yildiz Florencio Porto Freitas Felix C E Vogel Julianna Patricia Varga Jasmin Batani Christoph Bartenhagen Werner Schmitz Gabriele Büchel Bernhard Michalke Jashuo Zheng Svenja Meierjohann Enrico Girardi Elisa Espinet Andrés F Flórez Ancely Ferreira dos Santos Nesrine Aroua Tasneem Cheytan Julie Haenlin Lisa Schlicker Thamara N Xavier da Silva Adriana Przybylla Petra Zeisberger Giulio Superti‐Furga Martin Eilers Marcus Conrad Marietta Fabiano Ulrich Schweizer Matthias Fischer Almut Schulze Andreas Trumpp José Pedro Friedmann Angeli LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma EMBO Molecular Medicine ferroptosis neuroblastoma selenocysteine selenoprotein synthetic lethality |
| title | LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma |
| title_full | LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma |
| title_fullStr | LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma |
| title_full_unstemmed | LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma |
| title_short | LRP8‐mediated selenocysteine uptake is a targetable vulnerability in MYCN‐amplified neuroblastoma |
| title_sort | lrp8 mediated selenocysteine uptake is a targetable vulnerability in mycn amplified neuroblastoma |
| topic | ferroptosis neuroblastoma selenocysteine selenoprotein synthetic lethality |
| url | https://doi.org/10.15252/emmm.202318014 |
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