Mitochondrial double-stranded RNA fuels pancreatic cancer growth via RIG-I/TLR3 inflammation
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Andrew T. Milcarek
Genome Regulation and Cell Signaling Program, The Wistar Institute
Minjeong Yeon
Genome Regulation and Cell Signaling Program, The Wistar Institute
Camilla Esposito
Genome Regulation and Cell Signaling Program, The Wistar Institute
Prerna Kulkarni
Genome Regulation and Cell Signaling Program, The Wistar Institute
Andrew V. Kossenkov
Jozef Madzo
Genome Regulation and Cell Signaling Program, The Wistar Institute
Anneliese M. Faustino
Proteomics Shared Resource, The Wistar Institute
Hsin-Yao Tang
Alessandra M. Storaci
Department of Pathophysiology and Transplantation, University of Milan
Alessandro Palleschi
Division of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda-Ospedale Maggiore
Marco Locatelli
Division of Thoracic Surgery and Lung Transplantation, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda-Ospedale Maggiore Policlinico
Valentina Vaira
Department of Pathophysiology and Transplantation, University of Milan
Mary V. Iacocca
Department of Pathology, Helen F. Graham Cancer Center and Research Institute, Christiana Care Health
Andrea Ward
Department of Pathology, Helen F. Graham Cancer Center and Research Institute, Christiana Care Health
Arvind Sabesan
Helen F. Graham Cancer Center and Research Institute, Christiana Care Health
Nicholas J. Petrelli
Helen F. Graham Cancer Center and Research Institute, Christiana Care Health
Michela Perego
Genome Regulation and Cell Signaling Program, The Wistar Institute
Dario C. Altieri
Genome Regulation and Cell Signaling Program, The Wistar Institute