title: Distinctly perturbed metabolic networks underlie differential tumor tissue damages induced by immune modulator β-glucan in a two-case ex vivo non-small-cell lung cancer study.
abstract: Cancer and stromal cell metabolism is important for understanding tumor development, which highly depends on the tumor microenvironment (TME). Cell or animal models cannot recapitulate the human TME. We have developed an ex vivo paired cancerous (CA) and noncancerous (NC) human lung tissue approach to explore cancer and stromal cell metabolism in the native human TME. This approach enabled full control of experimental parameters and acquisition of individual patient's target tissue response to therapeutic agents while eliminating interferences from genetic and physiological variations. In this two-case study of non-small-cell lung cancer, we performed stable isotope-resolved metabolomic (SIRM) experiments on paired CA and NC lung tissues treated with a macrophage activator β-glucan and (13)C6-glucose, followed by ion chromatography-Fourier transform mass spectrometry (IC-FTMS) and nuclear magnetic resonance (NMR) analyses of (13)C-labeling patterns of metabolites. We demonstrated that CA lung tissue slices were metabolically more active than their NC counterparts, which recapitulated the metabolic reprogramming in CA lung tissues observed in vivo. We showed β-glucan-enhanced glycolysis, Krebs cycle, pentose phosphate pathway, antioxidant production, and itaconate buildup in patient UK021 with chronic obstructive pulmonary disease (COPD) and an abundance of tumor-associated macrophages (TAMs) but not in UK049 with no COPD and much less macrophage infiltration. This metabolic response of UK021 tissues was accompanied by reduced mitotic index, increased necrosis, and enhaced inducible nitric oxide synthase (iNOS) expression. We surmise that the reprogrammed networks could reflect β-glucan M1 polarization of human macrophages. This case study presents a unique opportunity for investigating metabolic responses of human macrophages to immune modulators in their native microenvironment on an individual patient basis.
authors.affiliation: Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA;
authors.forename: Teresa W-M
authors.initials: TW
authors.lastname: Fan
authors.affiliation: Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA;
authors.forename: Marc O
authors.initials: MO
authors.lastname: Warmoes
authors.affiliation: Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA;
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA;
authors.forename: Huan
authors.initials: H
authors.lastname: Song
authors.affiliation: Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA;
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turchan-Cholewo
authors.affiliation: Department of Surgery and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Jeremiah T
authors.initials: JT
authors.lastname: Martin
authors.affiliation: Department of Surgery and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Mahan
authors.affiliation: Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA;
authors.forename: Richard M
authors.initials: RM
authors.lastname: Higashi
authors.affiliation: Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA;
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Lane
keywords: immune dysregulation; increased inflammatory response; neoplasm of the lung; progressive pulmonary function impairment