Mitochondrial double stranded RNA Dependent Lipid Reprogramming in Non-Small Cell Lung Cancer
Transcription of the mitochondrial genome results in the generation of double stranded RNA. Escape of mitochondrial double stranded RNA (mtdsRNA) into the cytosol is deleterious and functions as a class of damage associated molecular pathogens (DAMPs) that elicits activation of an anti-viral response in cells. To mitigate the harmful consequences of excess cytosolic mtdsRNA, mammalian cells rely on the mitochondria localized exonuclease polynucleotide phosphorylase (PNPase) to degrade excess mtdsRNA. While the regulation of mtdsRNA by PNPase has been studied in the non-cancerous cells and tissue(s), less is known about the role PNPase plays in cancer cells nor the cellular consequences that PNPase inhibition and the dysregulation of mtdsRNA degradation has on tumor cells. Here, we demonstrate that PNPase inactivation in a Kras-driven, Lkb1 mutant (KL) genetically engineered mouse model (GEMM) of lung cancer resulted in a significant extension in overall survival of mice and reduced tumor cell proliferation. PNPase loss activated a robust interferon-stimulated viral mimicry response in lung tumors that triggered reprograming of lipid metabolism and upregulation of lipid droplet biogenesis in tumor cells. Tumors that escaped PNPase loss transformed into fatty lesions characterized by a substantial accumulation of lipid droplets enriched for polyunsaturated fatty acids (PUFAs). Importantly, PNPase null KL tumors were highly sensitive to ferroptosis, which resulted in the ablation and near complete clearance of tumors from the lung of mice. Similarly, targeted pharmacological inhibition of PNPase sensitized therapy resistant human lung and pancreatic tumor cells to ferroptosis. These findings demonstrate that PNPase represents a new class of molecular target and identified that viral mimicry and lipid droplet biogenesis may be readily exploited for the treatment of therapy resistant lung and pancreatic tumors. Overall design: Slow frozen tumours from KLluc and KLPNluc mice (90% FBS and 10% DMSO) were thawed on ice and dissociated in single cell as per 10X guidelines. Sequencing was carried out by UCLA's genomics core.