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

Hiroshi Kondo,Colin D.H Ratcliffe,Steven Hooper,James Ellis,James I Macrae,Marc Hennequart,Christopher W Dunsby,Kurt I Anderson,Erik Sahai

doi:10.1016/j.celrep.2021.108750

Hiroshi Kondo, Colin D.H Ratcliffe + Show 7 more

Open Access

https://doi.org/10.1016/j.celrep.2021.108750

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Abstract

SummaryInter-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.

Highlights

Intra-tumor heterogeneity presents a challenge for our understanding of cancer biology and cancer therapy
Breast cancer cells exhibit heterogeneity in metabolic state even under controlled culture conditions To study heterogeneity in metabolic state in breast cancer models, we first used a glucose fluorescence resonance energy transfer (FRET) biosensor based on the bacterial MglB protein (Figure 1A; Takanaga et al, 2008)
The biosensor did not affect the growth of cells stably expressing the fusion protein; a glucosedefective sensor was used as a control (Figure S1A)

Summary

Introduction

Intra-tumor heterogeneity presents a challenge for our understanding of cancer biology and cancer therapy. Metabolic intra-tumor heterogeneity and cellular transitions between metabolic states are difficult to observe Imaging modalities such as 18F-FDG PET/CT and hyper-polarized magnetic resonance imaging (MRI) can distinguish between metabolic states in tumors, but they lack the resolution to study heterogeneity at the cellular level (Andreet al., 2019; Bertero et al, 2019; Di Leo et al, 2018; Janku et al, 2018). Heterogeneity at this level and switching between metabolic states present a challenge to targeted therapies, including those targeting metabolic regulation directly and those targeting upstream signaling that controls metabolic programs (Hulea et al, 2018)

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