Single-Cell Kinetic Modeling of beta-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma

• Type of Material: Article
• Authors: Andrew D Raddatz, Emory University; Cristina M Furdui, Wake Forest School of Medicine, Winston-Salem; Erik A Bey, Wood Hudson Cancer Research Laboratory; Melissa Kemp, Emory University
• Language: English
• Date: 2023-03-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/antiox12030741
• Title of Journal or Parent Work: ANTIOXIDANTS
• Volume: 12
• Issue: 3
• Grant/Funding Information: This research was funded by the National Cancer Institute Cancer Systems Biology Consortium grant awarded to M.K., C.M.F. and E.A.B. grant number U01 CA215848 and by a National Institutes of Health Cell and Tissue Engineering T32 training grant awarded to A.R., GM145735.
• Keywords: Chemistry, Medicinal; ROS; systems modeling; redox biology; Science & Technology; REDOX METABOLISM; NRF2; Life Sciences & Biomedicine; Food Science & Technology; HYDROGEN-PEROXIDE; CANCER-CELLS; scRNA-seq; GENE; Pharmacology & Pharmacy; CHALLENGES; Biochemistry & Molecular Biology; beta-lapachone; head and neck squamous cell carcinoma
• Research Categories: Engineering, Biomedical

Abstract

Head and neck squamous cell carcinoma (HNSCC) cells are highly heterogeneous in their metabolism and typically experience elevated reactive oxygen species (ROS) levels such as superoxide and hydrogen peroxide (H2O2) in the tumor microenvironment. Tumor cells survive under these chronic oxidative conditions by upregulating antioxidant systems. To investigate the heterogeneity of cellular responses to chemotherapeutic H2O2 generation in tumor and healthy tissue, we leveraged single-cell RNA-sequencing (scRNA-seq) data to perform redox systems-level simulations of quinone-cycling β-lapachone treatment as a source of NQO1-dependent rapid superoxide and hydrogen peroxide (H2O2) production. Transcriptomic data from 10 HNSCC patient tumors was used to populate over 4000 single-cell antioxidant enzymatic network models of drug metabolism. The simulations reflected significant systems-level differences between the redox states of healthy and cancer cells, demonstrating in some patient samples a targetable cancer cell population or in others statistically indistinguishable effects between non-malignant and malignant cells. Subsequent multivariate analyses between healthy and malignant cellular models pointed to distinct contributors of redox responses between these phenotypes. This model framework provides a mechanistic basis for explaining mixed outcomes of NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable therapeutics despite the tumor specificity of these drugs as defined by NQO1/catalase expression and highlights the role of alternate antioxidant components in dictating drug-induced oxidative stress.