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

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, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E. Capen, Enzo Medico, Murat Cetinbas, Ruslan I. Sadreyev, Dennis Brown, Miguel N. Rivera, Anna Sapino, David T. Breault, Nathalie Y. R. Agar and Raul Mostoslavsky ()
Additional contact information
Carlos Sebastian: IRCCS
Christina Ferrer: Harvard Medical School
Maria Serra: IRCCS
Jee-Eun Choi: Harvard Medical School
Nadia Ducano: IRCCS
Alessia Mira: IRCCS
Manasvi S. Shah: Boston Children’s Hospital
Sylwia A. Stopka: Harvard Medical School
Andrew J. Perciaccante: Harvard Medical School
Claudio Isella: IRCCS
Daniel Moya-Rull: IRCCS
Marianela Vara-Messler: University of Torino
Silvia Giordano: IRCCS
Elena Maldi: IRCCS
Niyati Desai: Massachusetts General Hospital and Harvard Medical School
Diane E. Capen: Massachusetts General Hospital and Harvard Medical School
Enzo Medico: IRCCS
Murat Cetinbas: Massachusetts General Hospital and Harvard Medical School
Ruslan I. Sadreyev: Massachusetts General Hospital and Harvard Medical School
Dennis Brown: Massachusetts General Hospital and Harvard Medical School
Miguel N. Rivera: Harvard Medical School
Anna Sapino: IRCCS
David T. Breault: Boston Children’s Hospital
Nathalie Y. R. Agar: Harvard Medical School
Raul Mostoslavsky: Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29085-y

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