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Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.

ABSTRACT: Intracellular and environmental cues result in heterogeneous cancer cell populations with different metabolic and migratory behaviors. Although glucose metabolism and epithelial-to-mesenchymal transition have previously been linked, we aim to understand how this relationship fuels cancer cell migration. We show that while glycolysis drives single-cell migration in confining microtracks, fast and slow cells display different migratory sensitivities to glycolysis and oxidative phosphorylation inhibition. Phenotypic sorting of highly and weakly migratory subpopulations (MDA⁺, MDA^-) reveals that more mesenchymal, highly migratory MDA⁺ preferentially use glycolysis while more epithelial, weakly migratory MDA^- utilize mitochondrial respiration. These phenotypes are plastic and MDA⁺ can be made less glycolytic, mesenchymal, and migratory and MDA^- can be made more glycolytic, mesenchymal, and migratory via modulation of glucose metabolism or EMT. These findings reveal an intrinsic link between EMT and glucose metabolism that controls migration. Identifying mechanisms fueling phenotypic heterogeneity is essential to develop targeted metastatic therapeutics.

SUBMITTER: Schwager SC

PROVIDER: S-EPMC9579510 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.

Schwager Samantha C SC Mosier Jenna A JA Padmanabhan Reethi S RS White Addison A Xing Qinzhe Q Hapach Lauren A LA Taufalele Paul V PV Ortiz Ismael I Reinhart-King Cynthia A CA

iScience 20221001 10

Intracellular and environmental cues result in heterogeneous cancer cell populations with different metabolic and migratory behaviors. Although glucose metabolism and epithelial-to-mesenchymal transition have previously been linked, we aim to understand how this relationship fuels cancer cell migration. We show that while glycolysis drives single-cell migration in confining microtracks, fast and slow cells display different migratory sensitivities to glycolysis and oxidative phosphorylation inhi ...[more]

PMID: 36274934

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Project description:(1) Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity. The epithelial-mesenchymal transition (EMT) is one of the inducers of cancer metastasis and migration. However, the description of the EMT process in TNBC using single-cell RNA sequencing (scRNA-seq) remains unclear. (2) Methods: In this study, we analyzed 8938 cellular gene expression profiles from five TNBC patients. We first scored each malignant cell based on functional pathways to determine its EMT characteristics. Then, a pseudo-time trajectory analysis was employed to characterize the cell trajectories. Furthermore, CellChat was used to identify the cellular communications. (3) Results: We identified 888 epithelium-like and 846 mesenchyme-like malignant cells, respectively. A further pseudo-time trajectory analysis indicated the transition trends from epithelium-like to mesenchyme-like in malignant cells. To characterize the potential regulators of the EMT process, we identified 10 dysregulated transcription factors (TFs) between epithelium-like and mesenchyme-like malignant cells, in which overexpressed forkhead box protein A1 (FOXA1) was recognized as a poor prognosis marker of TNBC. Furthermore, we dissected the cell-cell communications via ligand-receptor (L-R) interactions. We observed that tumor-associated macrophages (TAMs) may support the invasion of malignant epithelial cells, based on CXCL-CXCR2 signaling. The tumor necrosis factor (TNF) signaling pathway secreted by TAMs was identified as an outgoing communication pattern, mediating the communications between monocytes/TAMs and malignant epithelial cells. Alternatively, the TNF-related ligand-receptor (L-R) pairs showed promising clinical implications. Some immunotherapy and anti-neoplastic drugs could interact with the L-R pairs as a potential strategy for the treatment of TNBC. In summary, this study enhances the understanding of the EMT process in the TNBC microenvironment, and dissections of EMT-related cell communications also provided us with potential treatment targets.

Dataset Information

Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.

Publications

Link between glucose metabolism and epithelial-to-mesenchymal transition drives triple-negative breast cancer migratory heterogeneity.

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