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| Item Type: | Article |
|---|---|
| Title: | Senescence-associated reprogramming promotes cancer stemness |
| Creators Name: | Milanovic, M., Fan, D.N.Y., Belenki, D., Däbritz, J.H.M., Zhao, Z., Yu, Y., Dörr, J.R., Dimitrova, L., Lenze, D., Monteiro Barbosa, I.A., Mendoza-Parra, M.A., Kanashova, T., Metzner, M., Pardon, K., Reimann, M., Trumpp, A., Dörken, B., Zuber, J., Gronemeyer, H., Hummel, M., Dittmar, G., Lee, S. and Schmitt, C.A. |
| Abstract: | Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16(INK4a), p21(CIP1) and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells. |
| Keywords: | B-Cell Lymphoma, Cancer Stem Cells, Mechanisms of Disease, Senescence, Animals, Mice |
| Source: | Nature |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Volume: | 553 |
| Number: | 7686 |
| Page Range: | 96-100 |
| Date: | 4 January 2018 |
| Additional Information: | Copyright © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. |
| Official Publication: | https://doi.org/10.1038/nature25167 |
| PubMed: | View item in PubMed |
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