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

Authors :
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
Raul Mostoslavsky
Source :
Nature communications. 13(1)
Publication Year :
2021

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.

Details

ISSN :
20411723
Volume :
13
Issue :
1
Database :
OpenAIRE
Journal :
Nature communications
Accession number :
edsair.doi.dedup.....f471bae37e18c504749fa980c683e5f1