Regulation of Bi-organellar CHCHD2 in Response to Hypoxia is Dependent upon EGFR Molecular Subtype in Glioblastoma

Glioblastoma (GBM) is the most common and malignant form of brain cancer in adults, with a median survival time of 12–15 mo. Tumors are heterogeneous and characterized by hypoxic foci. Amplification, overexpression, and mutation of the receptor tyrosine kinase (RTK) EGFR are prevalent in GBM, and the constitutively active EGFRvIII mutant shows the poorest clinical outcomes. However, RTK inhibitors have failed clinically against GBM, with EGFR subtype poorly predicting outcome. We are investigating compensatory signaling pathways active within GBM tumor margins as a possible source of resistance to molecular subtype therapies. Previous studies have reported coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2) as a bi-organellar protein localized predominantly in the mitochondrial inner membrane but also present in the nucleus where it acts as a transcription factor. We hypothesized that this co-localization enables GBM cells to adapt to hypoxic stress in the tumor microenvironment, part...