Proceedings of the National Academy of Sciences of the United States of America · 2026
Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation.
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Milcarek Andrew T, Yeon Minjeong, Esposito Camilla, Kulkarni Prerna, Kossenkov Andrew V, Madzo Jozef, Faustino Anneliese M, Tang Hsin-Yao, Storaci Alessandra M, Palleschi Alessandro, Locatelli Marco, Vaira Valentina, Iacocca Mary V, Ward Andrea, Sabesan Arvind, Petrelli Nicholas J, Perego Michela, Altieri Dario C
Аннотация
Mitochondria activate inflammation and innate immunity to protect against infections, but the role in cancer is unknown. Here, we report that patients with pancreatic ductal adenocarcinoma (PDAC) with reduced levels of the mitochondrial scaffold, Mic60, or inner mitochondrial membrane protein, exhibit increased inflammation, high NFκB activity and production of TNFα. This is mediated by double-stranded RNA (dsRNA) released from structurally defective, Mic60-low mitochondria, which engages TLR3/RIG-I sensing, activates NFκB gene expression and reprograms transcriptional and signaling networks to promote PDAC proliferation. Preclinical targeting of mitochondrial dsRNA signaling triggers rapid cell death and inhibition of tumor growth, selectively in Mic60-knockdown PDAC, without overt toxicity, in vivo. Therefore, dsRNA released from defective mitochondria generates protumorigenic inflammation and provides an actionable therapeutic target in selected PDAC patients.