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Synthetic lethal metabolic targeting of cellular senescence in cancer therapy

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Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3)1,2. Although therapy-induced senescence (TIS) improves long-term outcomes3, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1 lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously4,5,6. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.

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Figure 1: TIS is a highly glucose-consuming and energy-producing condition.
Figure 2: Selective vulnerability of TIS cells to inhibition of energy-generating catabolic pathways.
Figure 3: TIS shows a proteotoxic stress cascade.
Figure 4: Synthetic lethal targeting of TIS-related metabolic liabilties.

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Accession codes


Gene Expression Omnibus

Data deposits

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

Change history

  • 20 August 2013

    Source Data files for Figs 1–4 were added.


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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).

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Authors and Affiliations



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.

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Correspondence to Clemens A. Schmitt.

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The authors declare no competing financial interests.

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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).

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