Senescence-associated reprogramming promotes cancer stemness
Top Cited Papers
- 20 December 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 553 (7686), 96-100
- https://doi.org/10.1038/nature25167
Abstract
Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells1,2. Key signalling components of the senescence machinery, such as p16INK4a, p21CIP1 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’)3. 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.This publication has 61 references indexed in Scilit:
- Synthetic lethal metabolic targeting of cellular senescence in cancer therapyNature, 2013
- A Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA InterferenceCell, 2011
- A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription ProgramsCell, 2010
- The promises and perils of p53Nature, 2009
- MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantificationNature Biotechnology, 2008
- Growth-Inhibitory and Tumor- Suppressive Functions of p53 Depend on Its Repression of CD44 ExpressionCell, 2008
- Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem CellsCell Stem Cell, 2008
- Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their ProgenyCell Stem Cell, 2007
- Probing tumor phenotypes using stable and regulated synthetic microRNA precursorsNature Genetics, 2005
- The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic miceNature, 1985