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.