s41467-019-08839-1.pdf (8.47 MB)
Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses
journal contributionposted on 2019-12-16, 17:37 authored by Ivana Kurelac, Luisa Iommarini, Renaud Vatrinet, Laura Benedetta Amato, Monica De Luise, Giulia Leone, Giulia Girolimetti, Nikkitha Umesh Ganesh, Victoria Louise Bridgeman, Luigi Ombrato, Marta Columbaro, Moira Ragazzi, Lara Gibellini, Manuela Sollazzo, Rene Gunther Feichtinger, Silvia Vidali, Maurizio Baldassarre, Sarah Foriel, Michele Vidone, Andrea Cossarizza, Daniela Grifoni, Barbara Kofler, Ilaria Malanchi, Anna Maria Porcelli, Giuseppe Gasparre
Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials.
Adenoma, OxyphilicAminopyridinesAnimalsAntineoplastic AgentsCell Line, TumorCell ProliferationDrosophilaElectron Transport Complex IFemaleGene Knockout TechniquesHCT116 CellsHumansHypoxia-Inducible Factor 1, alpha SubunitMacrophagesMetforminMiceMice, KnockoutMice, NudeNADH DehydrogenaseNeovascularization, PathologicPyrrolesXenograft Model Antitumor AssaysMalanchi FC001112BRF-ackHP-ackFC-ack