Combined proteomics and CRISPR‒Cas9 screens in PDX identify ADAM10 as essential for leukemia in vivo

Molecular Cancer

Research

Rupert Öllinger¹  Matthias Mann²  Sophie Kreissig³  Christian Wichmann³  Roland Rad⁴  Maria Solovey⁵  Frank Ziemann⁶  Joris Maximilian Frenz⁷  Ashok Kumar Jayavelu⁸  Ehsan Bahrami⁹  Martin Becker⁹  Anna-Katharina Wirth⁹  Diana Amend⁹  Katharina Hunt⁹  Tania Vanessa Duque Angel⁹  Jan Philipp Schmid^1,10  Binje Vick^1,10  Romina Ludwig^1,10  Irmela Jeremias^1,11  Tobias Herold^1,12  Vindi Jurinovic^1,13 

[1] Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, and Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany;Institute of Molecular Oncology and Functional Genomics, Technische Universität München, Munich, Germany;Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany;Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, LMU University Hospital, LMU Munich, Munich, Germany;German Cancer Consortium (DKTK), partner site Munich, Munich, Germany;Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, and Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany;Institute of Molecular Oncology and Functional Genomics, Technische Universität München, Munich, Germany;Institute of Computational Biology, Helmholtz Center Munich, Munich, Germany;Chair of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, Munich, Germany;Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany;Proteomics and Cancer Cell Signaling Group, German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg and Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany;Proteomics and Cancer Cell Signaling Group, German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg and Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany;Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany;Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Center Munich, Feodor-Lynen-Str. 21, 81377, Munich, Germany;Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Center Munich, Feodor-Lynen-Str. 21, 81377, Munich, Germany;German Cancer Consortium (DKTK), partner site Munich, Munich, Germany;Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Center Munich, Feodor-Lynen-Str. 21, 81377, Munich, Germany;German Cancer Consortium (DKTK), partner site Munich, Munich, Germany;Department of Pediatrics, Dr. Von Hauner Children’s Hospital, LMU University Hospital, LMU Munich, Munich, Germany;Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Center Munich, Feodor-Lynen-Str. 21, 81377, Munich, Germany;German Cancer Consortium (DKTK), partner site Munich, Munich, Germany;Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany;Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Center Munich, Feodor-Lynen-Str. 21, 81377, Munich, Germany;Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany;

关键词: CRISPR-Cas9 in vivo screen;    Proteomics;    ADAM10;    PDX;    Acute leukemia;    Leukemia stem cells;   

DOI  :  10.1186/s12943-023-01803-0

 received in 2022-10-01, accepted in 2023-06-08,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAcute leukemias represent deadly malignancies that require better treatment. As a challenge, treatment is counteracted by a microenvironment protecting dormant leukemia stem cells.MethodsTo identify responsible surface proteins, we performed deep proteome profiling on minute numbers of dormant patient-derived xenograft (PDX) leukemia stem cells isolated from mice. Candidates were functionally screened by establishing a comprehensive CRISPR‒Cas9 pipeline in PDX models in vivo.ResultsA disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) was identified as an essential vulnerability required for the survival and growth of different types of acute leukemias in vivo, and reconstitution assays in PDX models confirmed the relevance of its sheddase activity. Of translational importance, molecular or pharmacological targeting of ADAM10 reduced PDX leukemia burden, cell homing to the murine bone marrow and stem cell frequency, and increased leukemia response to conventional chemotherapy in vivo.ConclusionsThese findings identify ADAM10 as an attractive therapeutic target for the future treatment of acute leukemias.

【 授权许可】

CC BY   
© The Author(s) 2023

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