Mapping Mitochondrial-localized mRNA Translational Rewiring in Radiation-resistant Pediatric DIPG

Dr. Furqan Fazal, Ph.D. – Baylor College of Medicine, Houston, TX

Diffuse intrinsic pontine glioma (DIPG) remains one of the most devastating pediatric cancers, with a median survival of less than one year and no effective therapies beyond radiotherapy. Despite decades of effort, chemotherapeutic interventions have failed to extend survival, in part due to intrinsic and acquired resistance to radiation. The urgent unmet clinical need for novel therapeutic strategies underscores the importance of uncovering fundamental biological mechanisms that enable DIPG survival under therapeutic stress. Mitochondria have emerged as central players in therapy resistance across many tumor types, and accumulating evidence suggests that DIPG is particularly dependent on mitochondrial oxidative phosphorylation (OXPHOS) for growth and survival. In particular, DIPG cells exhibit heightened OXPHOS activity and maintain metabolic flexibility that supports survival following radiation. Disruption of mitochondrial function can radiosensitize glioma cells, yet these approaches have shown limited translation to the clinic, in part because the systems-level rewiring of mitochondrial gene expression and local translation in DIPG remains poorly understood. This proposal addresses that gap by applying APEX-seq (Fazal et al., Cell 2019), an RNA proximity labeling approach we developed, to map the landscape of mitochondrial RNA localization and local translation in DIPG cells pre- and postradiotherapy.