Single-cell resolved imaging reveals intra-tumor heterogeneity in glycolysis, transitions between metabolic states, and their regulatory mechanisms.

Autor:	Kondo H; Tumor Cell Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., Ratcliffe CDH; Tumor Cell Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., Hooper S; Tumor Cell Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., Ellis J; Metabolomics Science Technology Platform, The Francis Crick Institute, London, NW1 1AT, UK., MacRae JI; Metabolomics Science Technology Platform, The Francis Crick Institute, London, NW1 1AT, UK., Hennequart M; p53 and Metabolism Laboratory, The Francis Crick Institute, London, NW1 1AT, UK., Dunsby CW; Photonics Group, Physics Department, Imperial College London, London, SW7 2AZ, UK., Anderson KI; Crick Advanced Light Microscopy Facility, The Francis Crick Institute, London, NW1 1AT, UK. Electronic address: kurt.anderson@crick.ac.uk., Sahai E; Tumor Cell Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK. Electronic address: erik.sahai@crick.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Feb 16; Vol. 34 (7), pp. 108750.
DOI:	10.1016/j.celrep.2021.108750
Abstrakt:	Inter-cellular heterogeneity in metabolic state has been proposed to influence many cancer phenotypes, including responses to targeted therapy. Here, we track the transitions and heritability of metabolic states in single PIK3CA mutant breast cancer cells, identify non-genetic glycolytic heterogeneity, and build on observations derived from methods reliant on bulk analyses. Using fluorescent biosensors in vitro and in tumors, we have identified distinct subpopulations of cells whose glycolytic and mitochondrial metabolism are regulated by combinations of phosphatidylinositol 3-kinase (PI3K) signaling, bromodomain activity, and cell crowding effects. The actin severing protein cofilin, as well as PI3K, regulates rapid changes in glucose metabolism, whereas treatment with the bromodomain inhibitor slowly abrogates a subpopulation of cells whose glycolytic activity is PI3K independent. We show how bromodomain function and PI3K signaling, along with actin remodeling, independently modulate glycolysis and how targeting these pathways affects distinct subpopulations of cancer cells. Competing Interests: Declaration of interests E.S. is a member of the scientific advisory board of Phenomic. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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