Senescence-associated reprogramming promotes cancer stemness

Maja Milanovic, Dorothy N.Y. Fan, Dimitri Belenki, J. Henry M. Däbritz, Zhen Zhao, Yong Yu, Jan R. Dörr, Lora Dimitrova, Dido Lenze, Ines A. Monteiro Barbosa, Marco A. Mendoza-Parra, Tamara Kanashova, Marlen Metzner, Katharina Pardon, Maurice Reimann, Andreas Trumpp, Bernd Dörken, Johannes Zuber, Hinrich Gronemeyer, Michael HummelGunnar Dittmar, Soyoung Lee, Clemens A. Schmitt*

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    477 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)96-100
    Number of pages5
    JournalNature
    Volume553
    Issue number7686
    DOIs
    Publication statusPublished - 4 Jan 2018

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