10779/crick.11371848.v1 Ivana Kurelac Ivana Kurelac Luisa Iommarini Luisa Iommarini Renaud Vatrinet Renaud Vatrinet Laura Benedetta Amato Laura Benedetta Amato Monica De Luise Monica De Luise Giulia Leone Giulia Leone Giulia Girolimetti Giulia Girolimetti Nikkitha Umesh Ganesh Nikkitha Umesh Ganesh Victoria Louise Bridgeman Victoria Louise Bridgeman Luigi Ombrato Luigi Ombrato Marta Columbaro Marta Columbaro Moira Ragazzi Moira Ragazzi Lara Gibellini Lara Gibellini Manuela Sollazzo Manuela Sollazzo Rene Gunther Feichtinger Rene Gunther Feichtinger Silvia Vidali Silvia Vidali Maurizio Baldassarre Maurizio Baldassarre Sarah Foriel Sarah Foriel Michele Vidone Michele Vidone Andrea Cossarizza Andrea Cossarizza Daniela Grifoni Daniela Grifoni Barbara Kofler Barbara Kofler Ilaria Malanchi Ilaria Malanchi Anna Maria Porcelli Anna Maria Porcelli Giuseppe Gasparre Giuseppe Gasparre Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses The Francis Crick Institute 2019 Adenoma, Oxyphilic Aminopyridines Animals Antineoplastic Agents Cell Line, Tumor Cell Proliferation Drosophila Electron Transport Complex I Female Gene Knockout Techniques HCT116 Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit Macrophages Metformin Mice Mice, Knockout Mice, Nude NADH Dehydrogenase Neovascularization, Pathologic Pyrroles Xenograft Model Antitumor Assays Malanchi FC001112 BRF-ack HP-ack FC-ack 2019-12-16 17:37:54 Journal contribution https://crick.figshare.com/articles/journal_contribution/Inducing_cancer_indolence_by_targeting_mitochondrial_Complex_I_is_potentiated_by_blocking_macrophage-mediated_adaptive_responses/11371848 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.