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A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine

Author

Listed:
  • Carlos Sebastian

    (IRCCS
    Universitat de Barcelona (UB)
    Institut de Biomedicina de la Universitat de Barcelona (IBUB))

  • Christina Ferrer

    (Harvard Medical School
    Harvard Medical School)

  • Maria Serra

    (IRCCS)

  • Jee-Eun Choi

    (Harvard Medical School
    Harvard Medical School)

  • Nadia Ducano

    (IRCCS)

  • Alessia Mira

    (IRCCS)

  • Manasvi S. Shah

    (Boston Children’s Hospital)

  • Sylwia A. Stopka

    (Harvard Medical School
    Harvard Medical School)

  • Andrew J. Perciaccante

    (Harvard Medical School
    University of Georgia)

  • Claudio Isella

    (IRCCS
    University of Torino)

  • Daniel Moya-Rull

    (IRCCS
    University of Torino)

  • Marianela Vara-Messler

    (University of Torino
    UCLeuven)

  • Silvia Giordano

    (IRCCS
    University of Torino)

  • Elena Maldi

    (IRCCS)

  • Niyati Desai

    (Massachusetts General Hospital and Harvard Medical School)

  • Diane E. Capen

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Enzo Medico

    (IRCCS
    University of Torino)

  • Murat Cetinbas

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Ruslan I. Sadreyev

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Dennis Brown

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Miguel N. Rivera

    (Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Anna Sapino

    (IRCCS
    Department of Medical Sciences, University of Torino)

  • David T. Breault

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard University)

  • Nathalie Y. R. Agar

    (Harvard Medical School
    Harvard Medical School
    Dana Farber Cancer Institute)

  • Raul Mostoslavsky

    (Harvard Medical School
    Harvard Medical School
    The Broad Institute of Harvard and MIT)

Abstract

Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.

Suggested Citation

  • Carlos Sebastian & Christina Ferrer & Maria Serra & Jee-Eun Choi & Nadia Ducano & Alessia Mira & Manasvi S. Shah & Sylwia A. Stopka & Andrew J. Perciaccante & Claudio Isella & Daniel Moya-Rull & Maria, 2022. "A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29085-y
    DOI: 10.1038/s41467-022-29085-y
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    References listed on IDEAS

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