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Senescence-associated reprogramming promotes cancer stemness

Authors

  • M. Milanovic
  • D.N.Y. Fan
  • D. Belenki
  • J.H.M. Däbritz
  • Z. Zhao
  • Y. Yu
  • J.R. Dörr
  • L. Dimitrova
  • D. Lenze
  • I.A. Monteiro Barbosa
  • M.A. Mendoza-Parra
  • T. Kanashova
  • M. Metzner
  • K. Pardon
  • M. Reimann
  • A. Trumpp
  • B. Dörken
  • J. Zuber
  • H. Gronemeyer
  • M. Hummel
  • G. Dittmar
  • S. Lee
  • C.A. Schmitt

Journal

  • Nature

Citation

  • Nature 553 (7686): 96-100

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.


DOI

doi:10.1038/nature25167