| Title: |
Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses |
| Authors: |
Kurelac, I; Iommarinio, L; Vatrinet, R; Amato, LB; De Luise, M; Leone, G; Girolimetti, G; Ganesh, NU; Bridgeman, VL; Ombrato, L; Columbaro, M; Ragazzi, M; Gibellini, L; Sollazzo, M; Feichtinger, RG; Vidali, S; Baldassarre, M; Foriel, S; Vidone, M; Cossarizza, A; Grifoni, D; Kofler, B; Malanchi, I; Porcelli, AM; Gasparre, G |
| Publication Year: |
2019 |
| Collection: |
Queen Mary University of London: Queen Mary Research Online (QMRO) |
| Description: |
Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancerstrategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Herewe use genetic ablation of this enzyme to induce indolence in two cancer types, andshow 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 inabilityto respond to hypoxia, concordantly with the persistence of human oncocytomas. Wedemonstrate that CI-deficient tumors survive and carry out angiogenesis, despite theirinability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated mac-rophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneouspharmacological inhibition of CI function through metformin and macrophage infiltrationthrough PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basisfor an efficient combinatorial adjuvant therapy in clinical trials. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
NATURE COMMUNICATIONS; ARTN 903; https://qmro.qmul.ac.uk/xmlui/handle/123456789/69323 |
| DOI: |
10.1038/s41467-019-08839-1 |
| Availability: |
https://qmro.qmul.ac.uk/xmlui/handle/123456789/69323; https://doi.org/10.1038/s41467-019-08839-1 |
| Rights: |
Creative Commons Attribution 4.0 International License ; http://creativecommons.org/licenses/by/4.0/ ; © The Author(s) 2019 |
| Accession Number: |
edsbas.EEEABEE4 |
| Database: |
BASE |