Tunneling Nanotubes Mediate Adaptation of Glioblastoma Cells to Temozolomide and Ionizing Radiation Treatment

Silvana Valdebenito; Alessandra Audia; Krishna P L Bhat; George Okafo; Eliseo A Eugenin

doi:10.1016/j.isci.2020.101450

Tunneling Nanotubes Mediate Adaptation of Glioblastoma Cells to Temozolomide and Ionizing Radiation Treatment

iScience. 2020 Aug 13;23(9):101450. doi: 10.1016/j.isci.2020.101450. eCollection 2020 Sep 25.

Authors

Silvana Valdebenito¹, Alessandra Audia², Krishna P L Bhat², George Okafo³, Eliseo A Eugenin¹

Affiliations

¹ Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch (UTMB), Research Building 17, Fifth Floor, 105 11th Street, Galveston, TX 77555, USA.
² Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, M.D. Anderson, Houston, TX, USA.
³ GO Pharma-consulting Ltd., Welwyn, UK.

Abstract

Glioblastoma (GBM) is the most prevalent and aggressive tumor in the central nervous system. Surgical resection followed by concurrent radiotherapy (ionizing radiation [IR]) and temozolomide (TMZ) is the standard of care for GBM. However, a large subset of patients offer resistance or become adapted to TMZ due mainly to the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT). Thus, alternative mechanisms of MGMT deregulation have been proposed but are heretofore unproven. We show that heterogeneous GBM cells express tunneling nanotubes (TNTs) upon oxidative stress and TMZ/IR treatment. We identified that MGMT protein diffused from resistant to sensitive cells upon exposure to TMZ/IR, resulting in protection against cytotoxic therapy in a TNT-dependent manner. In vivo analysis of resected GBM tumors support our hypothesis that the MGMT protein, but not its mRNA, was associated with TNT biomarkers. We propose that targeting TNT formation could be an innovative strategy to overcome treatment resistance in GBM.

Keywords: Cancer; Cell Biology.

Abstract

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