Signaling-induced systematic repression of miRNAs uncovers cancer vulnerabilities and targeted therapy sensitivity

  • Cell Rep Med. 2023 Sep 12;101200. doi: 10.1016/j.xcrm.2023.101200.
Alexander A Wurm  1 ,  Silke Brilloff  2 ,  Sofia Kolovich  2 ,  Silvia Schäfer  2 ,  Elahe Rahimian  2 ,  Vida Kufrin  2 ,  Marius Bill  3 ,  Zunamys I Carrero  4 ,  Stephan Drukewitz  5 ,  Alexander Krüger  6 ,  Melanie Hüther  7 ,  Sebastian Uhrig  8 ,  Sandra Oster  6 ,  Dana Westphal  9 ,  Friedegund Meier  10 ,  Katrin Pfütze  11 ,  Daniel Hübschmann  12 ,  Peter Horak  13 ,  Simon Kreutzfeldt  13 ,  Daniela Richter  14 ,  Evelin Schröck  15 ,  Gustavo Baretton  6 ,  Christoph Heining  14 ,  Lino Möhrmann  14 ,  Stefan Fröhling  13 ,  Claudia R Ball  16 ,  Hanno Glimm  17
Affiliations
  • 1. Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany. Electronic address: [email protected].
  • 2. Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
  • 3. Mildred Scheel Early Career Center, National Center for Tumor Diseases (NCT/UCC) Dresden, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany.
  • 4. Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany.
  • 5. German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute of Human Genetics, University of Leipzig, Leipzig, Germany.
  • 6. German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
  • 7. Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
  • 8. Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
  • 9. Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • 10. Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Skin Cancer Center at the University Cancer Centre Dresden and National Center for Tumor Diseases, Dresden, Germany.
  • 11. German Cancer Consortium (DKTK), Heidelberg, Germany; Sample Processing Laboratory, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
  • 12. Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
  • 13. German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
  • 14. Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany.
  • 15. German Cancer Consortium (DKTK), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute for Clinical Genetics, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, Germany; ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany.
  • 16. Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Technische Universität Dresden, Faculty of Biology, Dresden, Germany.
  • 17. Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT/UCC) Dresden, a partnership between DKFZ, Faculty of Medicine of the Technische Universität Dresden, University Hospital Carl Gustav Carus Dresden, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
PMID: 37734378 DOI: 10.1016/j.xcrm.2023.101200
Abstract

Targeted therapies are effective in treating Cancer, but success depends on identifying Cancer vulnerabilities. In our study, we utilize small RNA Sequencing to examine the impact of pathway activation on MicroRNA (miRNA) expression patterns. Interestingly, we discover that miRNAs capable of inhibiting key members of activated pathways are frequently diminished. Building on this observation, we develop an approach that integrates a low-miRNA-expression signature to identify druggable target genes in Cancer. We train and validate our approach in colorectal Cancer cells and extend it to diverse Cancer models using patient-derived in vitro and in vivo systems. Finally, we demonstrate its additional value to support genomic and transcriptomic-based drug prediction strategies in a pan-cancer patient cohort from the National Center for Tumor Diseases (NCT)/German Cancer Consortium (DKTK) Molecularly Aided Stratification for Tumor Eradication (MASTER) precision oncology trial. In conclusion, our strategy can predict Cancer vulnerabilities with high sensitivity and accuracy and might be suitable for future therapy recommendations in a variety of Cancer subtypes.

Keywords
cancer driver; drug response; miRNA signatures; organoids; precision oncology; spheroids; target prediction.
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