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Nat Commun DOI:10.1038/s41467-022-29085-y

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

Publication TypeJournal Article
Year of Publication2022
AuthorsSebastián, C, Ferrer, C, Serra, M, Choi, J-E, Ducano, N, Mira, A, Shah, MS, Stopka, SA, Perciaccante, AJ, Isella, C, Moya-Rull, D, Vara-Messler, M, Giordano, S, Maldi, E, Desai, N, Capen, DE, Medico, E, Cetinbas, M, Sadreyev, RI, Brown, D, Rivera, MN, Sapino, A, Breault, DT, Agar, NYR, Mostoslavsky, R
JournalNat Commun
Date Published2022 Mar 21
KeywordsAnimals, Cell Transformation, Neoplastic, Glycolysis, Intestines, Mice, Neoplasms, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Sirtuins

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 APC 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.


Alternate JournalNat Commun
PubMed ID35314684
Grant ListRC 2018 / / Ministero della Salute (Ministry of Health, Italy) /
R01 DK119488 / DK / NIDDK NIH HHS / United States
R01CA175727 / / U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) /
P30 DK034854 / DK / NIDDK NIH HHS / United States
R01GM128448 / / U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) /