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Senescence-associated reprogramming promotes cancer stemness
- Source :
- Nature, Nature, Nature Publishing Group, 2018, 553 (7686), pp.96-100. ⟨10.1038/nature25167⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Senescence
Cancer Research
Multidisciplinary
Wnt signaling pathway
Cancer
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Biology
Cell cycle
medicine.disease
3. Good health
03 medical and health sciences
030104 developmental biology
Cell culture
Cancer cell
Cancer research
medicine
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Technology Platforms
Stem cell
Reprogramming
ComputingMilieux_MISCELLANEOUS
Subjects
Details
- Language :
- English
- ISSN :
- 00280836 and 14764679
- Database :
- OpenAIRE
- Journal :
- Nature, Nature, Nature Publishing Group, 2018, 553 (7686), pp.96-100. ⟨10.1038/nature25167⟩
- Accession number :
- edsair.doi.dedup.....5693bfb1cf0313dd752edd8c15b9dce4
- Full Text :
- https://doi.org/10.1038/nature25167⟩