Synthetic lethal metabolic targeting of cellular senescence in cancer therapy (original) (raw)

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Accessions

Gene Expression Omnibus

Data deposits

Microarray data are deposited at the Gene Expression Omnibus under accession numbers GSE31099 and GSE44355.

Change history

Source Data files for Figs 1–4 were added.

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Acknowledgements

We thank the late A. Harris, T. Jacks, T. Jenuwein, P. A. Khavari, N. Mizushima, D. Peeper, and M. Vander Heiden for mice, cells and materials; the flow cytometry facility at the Berlin-Brandenburg Center for Regenerative Therapies; N. Burbach, J. Dräger, A. Herrmann, K. Kirste, S. Maßwig, B. Teichmann and S. Spiesicke-Wegener for technical assistance; and members of the Schmitt laboratory for discussions and editorial advice. This work was supported by a Ph.D. fellowship to J.R.D. from the Boehringer Ingelheim Foundation, and grants from the Deutsche Forschungsgemeinschaft to W.M.-K. (MK576/15-1), to U.K. and A.K.B. (SFB 824), to U.K., B.D., S.L. and C.A.S. (SFB/TRR 54), and to C.A.S. from the Helmholtz Association (Helmholtz Alliance ‘Preclinical Comprehensive Cancer Center’; grant no. HA-305) and the Deutsche Krebshilfe (grant no. 108789). This interdisciplinary work was made possible by the structural framework of the inter-institutional cooperation between Charité and MDC (now represented by the Berlin Institute of Health (BIH)), the Berlin School of Integrative Oncology (BSIO) graduate program funded within the Excellence Initiative, and the German Cancer Consortium (GCC).

Author information

Authors and Affiliations

  1. Charité-Universitätsmedizin Berlin, Molekulares Krebsforschungszentrum (MKFZ), Augustenburger Platz 1, 13353 Berlin, Germany,
    Jan R. Dörr, Maja Milanovic, J. Henry M. Däbritz, Jan Lisec, Anne Gerhardt, Katharina Schleicher, Bernd Dörken, Maurice Reimann, Soyoung Lee & Clemens A. Schmitt
  2. Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany,
    Yong Yu, Gregor Beuster, Bettina Purfürst, Bernd Dörken, Soyoung Lee & Clemens A. Schmitt
  3. Integrative Metabolomics and Proteomics, Berlin Institute of Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany,
    Christin Zasada & Stefan Kempa
  4. German Cancer Consortium, Deutsches Krebsforschungzentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany,
    Jan Lisec
  5. Department of Pathology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany,
    Dido Lenze & Michael Hummel
  6. III Medical Department, Technische Universität München, Ismaninger Straße 22, 81675 Munich, Germany,
    Susanne Kratzat & Ulrich Keller
  7. Universitätsmedizin der Johannes Gutenberg-Universität, Institute of Physiology and Pathophysiology, Duesbergweg 6, 55128 Mainz, Germany,
    Stefan Walenta & Wolfgang Mueller-Klieser
  8. Department of Anesthesiology and Intensive Care Medicine & Center for Sepsis Control and Care (CSCC), Universitätsklinikum Jena, Erlanger Allee 1, 07747 Jena, Germany,
    Markus Gräler
  9. Department of Nuclear Medicine, Universitätsklinikum Würzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany,
    Andreas K. Buck
  10. Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam, Germany,
    Lothar Willmitzer

Authors

  1. Jan R. Dörr
  2. Yong Yu
  3. Maja Milanovic
  4. Gregor Beuster
  5. Christin Zasada
  6. J. Henry M. Däbritz
  7. Jan Lisec
  8. Dido Lenze
  9. Anne Gerhardt
  10. Katharina Schleicher
  11. Susanne Kratzat
  12. Bettina Purfürst
  13. Stefan Walenta
  14. Wolfgang Mueller-Klieser
  15. Markus Gräler
  16. Michael Hummel
  17. Ulrich Keller
  18. Andreas K. Buck
  19. Bernd Dörken
  20. Lothar Willmitzer
  21. Maurice Reimann
  22. Stefan Kempa
  23. Soyoung Lee
  24. Clemens A. Schmitt

Contributions

J.R.D., S.L. and C.A.S. conceived the project, designed the experiments, and analysed the data, and W.M.-K., U.K., B.D., L.W. and St.K. provided critical input. Y.Y., G.B., C.Z., J.H.M.D., J.L., A.G., K.S., Su.K., S.W., M.G. and M.R. conducted experiments, M.M. compiled GSEA data, D.L. generated gene expression profiling data, M.H. analysed GEP data, B.P. carried out electron microscopy, and A.K.B. performed PET imaging. C.A.S., with editorial assistance from S.L., wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence toClemens A. Schmitt.

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Competing interests

The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Figures 1-16, Supplementary Table 1 and Supplementary References. (PDF 8227 kb)

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Dörr, J., Yu, Y., Milanovic, M. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.Nature 501, 421–425 (2013). https://doi.org/10.1038/nature12437

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