Glioblastoma cell motility depends on enhanced oxidative stress coupled with mobilization of a sulfurtransferase

Mirca S Saurty-Seerunghen (1, 2) , Thomas Daubon (3) , Léa Bellenger (4) , Virgile Delaunay (1, 2) , Gloria Castro (1, 2) , Joris Guyon (5) , Ahmed Rezk (1, 2) , Sylvie Fabrega (6) , Ahmed Idbaih (7) , Fabien Almairac (8, 9) , Fanny Burel-Vandenbos (9, 8) , Laurent Turchi (9, 8) , Eric Duplus (10) , Thierry Virolle (9) , Jean-Michel Peyrin (1, 2) , Christophe Antoniewski (4) , Hervé Chneiweiss (1, 2) , Elias El-Habr (1, 2) , Marie-Pierre Junier (1, 2)

1 NPS - Neuroscience Paris Seine
2 IBPS - Institut de Biologie Paris Seine
3 IBGC - Institut de biochimie et génétique cellulaires
4 IBPS-Artbio - Bioinformatique [IBPS]
5 Inserm U1312 - BRIC - BoRdeaux Institute in onCology
6 UAR 3633 / US24 - Structure Fédérative de Recherche Necker
7 ICM - Institut du Cerveau = Paris Brain Institute
8 CHU Nice - Centre Hospitalier Universitaire de Nice
9 IBV - Institut de Biologie Valrose
10 B2A-IBPS - Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing

Abstract Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients’ glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients’ tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients’ tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients’ tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.

Domaines: Sciences du Vivant [q-bio]; Biologie cellulaire

Mirca S Saurty-Seerunghen, Thomas Daubon, Léa Bellenger, Virgile Delaunay, Gloria Castro, et al.. Glioblastoma cell motility depends on enhanced oxidative stress coupled with mobilization of a sulfurtransferase. Cell Death and Disease, 2022, 13 (10), pp.913. ⟨10.1038/s41419-022-05358-8⟩. ⟨hal-03836497⟩