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

Autor: Sebastian C; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy. csebastian@ub.edu.; Departament de Biologia Cel.lular, Fisiologia i Immunologia, Facultad de Biologia, Universitat de Barcelona (UB), 08028, Barcelona, Spain. csebastian@ub.edu.; Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028, Barcelona, Spain. csebastian@ub.edu., Ferrer C; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA, 02114, USA., Serra M; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy., Choi JE; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA, 02114, USA., Ducano N; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy., Mira A; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy., Shah MS; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA., Stopka SA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Perciaccante AJ; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; University of Georgia, Athens, GA, USA., Isella C; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy.; Department of Oncology, University of Torino, Turin, Italy., Moya-Rull D; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy.; Department of Oncology, University of Torino, Turin, Italy., Vara-Messler M; Department of Oncology, University of Torino, Turin, Italy.; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Experimentale et Clinique (IREC), UCLeuven, Brussels, Belgium., Giordano S; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy.; Department of Oncology, University of Torino, Turin, Italy., Maldi E; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy., Desai N; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA., Capen DE; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.; Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA., Medico E; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy.; Department of Oncology, University of Torino, Turin, Italy., Cetinbas M; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA., Sadreyev RI; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA., Brown D; Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.; Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA., Rivera MN; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.; Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA., Sapino A; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Italy.; Department of Medical Sciences, University of Torino, Turin, Italy., Breault DT; Division of Endocrinology, Boston Children's Hospital, Boston, MA, 02115, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, 02138, USA., Agar NYR; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02115, USA., Mostoslavsky R; The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA. rmostoslavsky@mgh.harvard.edu.; The MGH Center for Regenerative Medicine, Harvard Medical School, Boston, MA, 02114, USA. rmostoslavsky@mgh.harvard.edu.; The Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. rmostoslavsky@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Mar 21; Vol. 13 (1), pp. 1503. Date of Electronic Publication: 2022 Mar 21.
DOI: 10.1038/s41467-022-29085-y
Abstrakt: 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 min 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: