TY - JOUR
T1 - Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses
AU - Kurelac, Ivana
AU - Iommarini, Luisa
AU - Vatrinet, Renaud
AU - Amato, Laura Benedetta
AU - De Luise, Monica
AU - Leone, Giulia
AU - Girolimetti, Giulia
AU - Umesh Ganesh, Nikkitha
AU - Bridgeman, Victoria Louise
AU - Ombrato, Luigi
AU - Columbaro, Marta
AU - Ragazzi, Moira
AU - Gibellini, Lara
AU - Sollazzo, Manuela
AU - Feichtinger, Rene Gunther
AU - Vidali, Silvia
AU - Baldassarre, Maurizio
AU - Foriel, Sarah
AU - Vidone, Michele
AU - Cossarizza, Andrea
AU - Grifoni, Daniela
AU - Kofler, Barbara
AU - Malanchi, Ilaria
AU - Porcelli, Anna Maria
AU - Gasparre, Giuseppe
PY - 2019/2/22
Y1 - 2019/2/22
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-08839-1
DO - 10.1038/s41467-019-08839-1
M3 - Article
C2 - 30796225
VL - 10
SP - 1
EP - 18
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -