Mitochondrial double stranded RNA Dependent Lipid Repropgramming in Non-Small Cell Lung Cancer

ABSTRACT: Transcription of the mitochondrial genome results in the generation of double stranded RNA. Escape of mitochondrial double stranded RNA (mtdsRNA) into the cytosol is harmful and functions as a class of damage associated molecular pathogen (DAMP) that elicits activation of an MDA5 driven anti-viral response in cells [PMID:30046113,38955468]. To mitigate the deleterious consequences of excess cytosolic mtdsRNA, mammalian cells rely on the mitochondria localized exonuclease polynucleotide phosphorylase (PNPase) to degrade excess mtdsRNA [PMID:20691904,38955468]. Little is known about the role of PNPase in cancer or the cellular consequences that PNPase inhibition and cytosolic mtdsRNA have on tumour cells. Here, we demonstrate that PNPase inactivation in a therapy-resistant Kras-driven, Lkb1 (KL) mutant genetically engineered mouse model (GEMM) of lung cancer resulted in a significant extension in overall survival of mice and reduced tumour cell proliferation. PNPase loss activated a robust interferon-stimulated viral mimicry response in lung tumours that triggered reprograming of lipid metabolism and upregulation of lipid droplet biogenesis in tumour cells. Tumours that escaped PNPase loss transformed into fatty lesions characterized by a massive accumulation of lipid droplets enriched for polyunsaturated fatty acids (PUFAs). Importantly, PNPase null KL tumours were highly sensitive to ferroptosis, a non-canonical form of cell death, which resulted in the near complete clearance of tumours from the lung of mice. Similarly, human lung and pancreatic tumour cells were equally sensitive to targeted pharmacological inhibition of PNPase in combination with ferroptosis induction. These findings identify PNPase as a critical regulator of tumour fate through control of mitochondrial regulated innate immunity and lipid droplet biogenesis, uncovering a new therapeutic vulnerability that may be exploited in therapy resistant lung and pancreatic tumours..

ORGANISM(S): Mus musculus

PROVIDER: GSE311846 | GEO | 2025/12/02

REPOSITORIES: GEO