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Nature. 2018 Jan 4;553(7686):96-100. doi: 10.1038/nature25167. Epub 2017 Dec 20.

Senescence-associated reprogramming promotes cancer stemness.

Author information

1
Charité - Universitätsmedizin Berlin, Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum - MKFZ, Virchow Campus, 13353 Berlin, Germany.
2
Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), 69120 Heidelberg, Germany.
3
German Cancer Research Center (Deutsches Krebsforschungszentrum - DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
4
Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner site Berlin, Berlin, Germany.
5
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
6
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
7
Charité - Universitätsmedizin Berlin, Department of Pathology, Berlin, Germany.
8
Institute of Molecular Pathology (IMP), Vienna Biocenter, Dr Bohr-Gasse 7, 1030 Vienna, Austria.
9
Equipe Labellisée Ligue Contre le Cancer, Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR7104, Institut National de la Santé et de la Recherche Médicale, U964, Université de Strasbourg, 67400 Illkirch, France.
10
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
11
Berlin Institute of Health, Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany.
12
Luxembourg Institute of Health, 1A-B rue Thomas Edison, L-1455 Strassen, Luxembourg.

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 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'). 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.

PMID:
29258294
DOI:
10.1038/nature25167
[Indexed for MEDLINE]

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