@article{94380c766b6547a58a828bd89113fe48,
title = "Single-cell resolved imaging reveals intra-tumor heterogeneity in glycolysis, transitions between metabolic states, and their regulatory mechanisms",
abstract = "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. Kondo et al. reveal metabolic heterogeneity in breast cancer by using biosensors, including variable coupling of PI3K to glycolysis. Glucose levels are linked to cell density by cofilin, enabling increased uptake by migrating cells. High-glucose cells grow slowly without pyruvate but are rescued by other cancer cells or stromal fibroblasts.",
keywords = "breast cancer, cofilin, FRET imaging, intra-tumor heterogeneity, intravital imaging, PI3K signaling, tumor metabolism",
author = "Hiroshi Kondo and Ratcliffe, {Colin D.H.} and Steven Hooper and James Ellis and MacRae, {James I.} and Marc Hennequart and Dunsby, {Christopher W.} and Anderson, {Kurt I.} and Erik Sahai",
note = "Funding Information: We thank Dmitrios Anastasiou and the Sahai laboratory for comments and advice. We thank the Crick Advanced Light Facility, Cell Services, Flow Cytometry, Metabolomics Science Technology Platform and the Biological Research facility for scientific and technical support. This research was funded by a grant from the Fonds de Recherche du Qu{\'e}bec - Sant{\'e} (C.D.H.R.) and the Francis Crick Institute (K.I.A. and E.S.), which receives its core funding from Cancer Research UK ( FC010144 ), the UK Medical Research Council ( FC010144 ), and the Wellcome Trust ( FC010144 ). H.K. received support from Cancer Research UK C7408/A28450 . Funding Information: We thank Dmitrios Anastasiou and the Sahai laboratory for comments and advice. We thank the Crick Advanced Light Facility, Cell Services, Flow Cytometry, Metabolomics Science Technology Platform and the Biological Research facility for scientific and technical support. This research was funded by a grant from the Fonds de Recherche du Qu{\'e}bec - Sant{\'e} (C.D.H.R.) and the Francis Crick Institute (K.I.A. and E.S.), which receives its core funding from Cancer Research UK (FC010144), the UK Medical Research Council (FC010144), and the Wellcome Trust (FC010144). H.K. received support from Cancer Research UK C7408/A28450. H.K. K.I.A. and E.S. conceived and developed the project. H.K. C.D.H.R. and S.H. performed the experiments and analyzed the data. J.E. and J.I.M. performed the analysis of metabolomic data. M.H. provided reagents. E.S. C.D.H.R. and H.K. wrote the manuscript with assistance from J.I.M. C.W.D. and K.I.A. E.S. is a member of the scientific advisory board of Phenomic. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = feb,
day = "16",
doi = "10.1016/j.celrep.2021.108750",
language = "English",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}