Tracking functional tumor cell subpopulations of malignant glioma by phasor fluorescence lifetime imaging microscopy of NADH

Andrew L. Trinh, Hongtao Chen, Yumay Chen, Yuanjie Hu, Zhenzhi Li, Eric R. Siegel, Mark E. Linskey, Ping H. Wang, Michelle A. Digman*, Yi Hong Zhou

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC) subpopulation relative to the tumor mass-forming cell (TMC) subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis), EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment.

Original languageEnglish (US)
Article number168
JournalCancers
Volume9
Issue number12
DOIs
StatePublished - Dec 2017

Keywords

  • Cellular bioenergetics
  • Fluorescence lifetime imaging microscopy (FLIM)
  • Intra-tumoral heterogeneity
  • Malignant glioma
  • Reduced nicotinamide adenine dinucleotide (NADH)
  • Stem-like tumor-initiating cells
  • Tumor cell subpopulation
  • Tumor mass cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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