Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses

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 () and Giuseppe Gasparre ()
Additional contact information
Ivana Kurelac: Università di Bologna
Luisa Iommarini: Università di Bologna
Renaud Vatrinet: Università di Bologna
Laura Benedetta Amato: Università di Bologna
Monica De Luise: Università di Bologna
Giulia Leone: Università di Bologna
Giulia Girolimetti: Università di Bologna
Nikkitha Umesh Ganesh: Università di Bologna
Victoria Louise Bridgeman: The Francis Crick Institute
Luigi Ombrato: The Francis Crick Institute
Marta Columbaro: IRCCS Istituto Ortopedico Rizzoli
Moira Ragazzi: Azienda Ospedaliera S. Maria Nuova di Reggio Emilia
Lara Gibellini: Università degli Studi di Modena e Reggio Emilia
Manuela Sollazzo: Università di Bologna
Rene Gunther Feichtinger: University Hospital of the Paracelsus Medical University
Silvia Vidali: University Hospital of the Paracelsus Medical University
Maurizio Baldassarre: Università di Bologna
Sarah Foriel: Khondrion BV
Michele Vidone: Università di Bologna
Andrea Cossarizza: Università degli Studi di Modena e Reggio Emilia
Daniela Grifoni: Università di Bologna
Barbara Kofler: University Hospital of the Paracelsus Medical University
Ilaria Malanchi: The Francis Crick Institute
Anna Maria Porcelli: Università di Bologna
Giuseppe Gasparre: Università di Bologna

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08839-1

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