Mitochondrial genetics in the progression of solid tumors

Attività scientifica

Our research group investigates the role of mitochondrial DNA mutations and their metabolic consequences as modifiers of cancer phenotype during solid neoplasia progression. Starting from peculiar models of short-circuited tumorigenesis, such as human oncocytomas, which are rare indolent types of tumors with unique cytological and histopathological features due to an aberrant mitochondrial hyperplasia, we unveil the anti-tumorigenic behavior of disruptive mutations of the respiratory chain, along with mechanisms of cancer adaptation. The main research stream separates, in collaboration with the mitochondrial biochemistry group coordinated by Prof. Porcelli at FABIT, into several branches concerning the effects of a bioenergetic deficit on the tumor microenvironment, with particular reference to the immune system component, on the cells ability to undergo epithelial-mesenchymal transition, and on the activation of compensatory pathways that may be targeted to trigger synthetic lethality. We also study the consequences of implementing respiratory complex I inhibitors in oncology, both repurposed and of de novo synthesis. With a specific focus on ovarian carcinoma, in collaboration with the Unit of gynecologic oncology at UNIBO, we investigate the mechanisms that underlie chemoresistance onset, in correlation with genetics and mitochondrial metabolism, as part of the Research and Study Center for Gynecologic Neoplasia. To this aim, we exploit 3D ex vivo perfusion-based cultures of human tumors. We receive funding from the Italian Association for Cancer Research (AIRC/FIRC), from the Italian Ministry of University and Research, the Worldwide Cancer Research, the Veronesi, the CARISBO and Del Monte Foundations, and from the European Union through ITN Marie Curie programmes (MEET – Mitochondrial European Educational Training, 7th Framework Programme; TRANSMIT – Translating the role of Mitochondria in Tumorigenesis, Horizon2020).

National and international collaborations

Dr. I.Malanchi – Francis Crick Institute London – Role of mitochondrial complex I in stroma-tumour interaction

Dr. R.Rossignol – INSERM, Università di Bordeaux, France – Bioenergetic profiles of cells null for complex I and p53

Prof. B.Kofler – Paracelsus Medical University, Salzburg, Austria – the role of complex I in decreasing tumour progression, in vivo studies

Dr. D.Meierhofer – Max Planck Institute, Berlin, germany – metabolic characteristics of sporadic and familial oncocytomas

Dr. P.Sancho – Translational Research Unit, IIS Aragon, Zaragoza, Spain – stemness and chemoresistance in ovarian carcinoma

Dr. C.Munoz-Pinedo - Bellvitge Biomedical Research Institute, Barcelona, Spain – starvation and cell death in metabolic collapse by Complex I inhibition

Dr. H.Nasiri – University of Frankfurt, Germany – newly synthesised pharmacological inhibitors of mitochondrial complex I

Dr. P.Ferraro - Consiglio Nazionale delle Ricerche (CNR), Istituto di Scienza Applicate e sistemi Intelligenti “Eduardo Cainiello” (ISASI) – Development of methods for identifying circulating tumour cells

Prof. M.Capasso - Università degli studi di Napoli Federico II, Dipartimento di Medicina Molecolare e Biotecnologie mediche - Development of methods for identifying circulating tumour cells

Scientific production

1.NDUFS3 knockout cancer cells and molecular docking reveal specificity and mode of action of anticancer respiratory Complex I inhibitors
Kurelac I, Cavina B, Sollazzo M, Fornasa A, De Luise M, Iorio M, Lama E, Traversa D, Nasiri HR, Ghelli A, Musiani F, Porcelli AM, Iommarini L, Gasparre. G Open Biol. In press.

2.Inducing respiratory complex I impairment elicits an increase in PGC1 in ovarian cancer.
De Luise M, Sollazzo M, Lama E, Coadă CA, Bressi L, Iorio M, Cavina B, D'Angelo L, Milioni S, Marchio L, Miglietta S, Coluccelli S, Tedesco G, Ghelli A, Lemma S, Perrone AM, Kurelac I, Iommarini L, Porcelli AM, Gasparre G. Sci Rep. 2022 May 16;12(1):8020. doi: 10.1038/s41598-022-11620-y.

3.NDUFS3 depletion permits complex I maturation and reveals TMEM126A/OPA7 as an assembly factor binding the ND4-module intermediate.
D'Angelo L, Astro E, De Luise M, Kurelac I, Umesh-Ganesh N, Ding S, Fearnley IM, Gasparre G, Zeviani M, Porcelli AM, Fernandez-Vizarra E, Iommarini L. Cell Rep. 2021 Apr 20;35(3):109002. doi: 10.1016/j.celrep.2021.109002.

4.Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses.
Kurelac I, Iommarini L, Vatrinet R, Amato LB, De Luise M, Leone G, Girolimetti G, Umesh Ganesh N, 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. Nat Commun. 2019 Feb 22;10(1):903. doi: 10.1038/s41467-019-08839-1.

5.Platinum-induced mitochondrial DNA mutations confer lower sensitivity to paclitaxel by impairing tubulin cytoskeletal organization.
Girolimetti G, Guerra F, Iommarini L, Kurelac I, Vergara D, Maffia M, Vidone M, Amato LB, Leone G, Dusi S, Tiranti V, Perrone AM, Bucci C, Porcelli AM, Gasparre G. Hum Mol Genet. 2017 Aug 1;26(15):2961-2974. doi: 10.1093/hmg/ddx186

6.Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells.
Calabrese C, Iommarini L, Kurelac I, Calvaruso MA, Capristo M, Lollini PL, Nanni P, Bergamini C, Nicoletti G, Giovanni CD, Ghelli A, Giorgio V, Caratozzolo MF, Marzano F, Manzari C, Betts CM, Carelli V, Ceccarelli C, Attimonelli M, Romeo G, Fato R, Rugolo M, Tullo A, Gasparre G, Porcelli AM. Cancer Metab. 2013 Mar 18;1(1):11. doi: 10.1186/2049-3002-1-11.

7.Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment
Iommarini L, Kurelac I, Capristo M, Calvaruso MA, Giorgio V, Bergamini C, Ghelli A, Nanni P, De Giovanni C, Carelli V, Fato R, Lollini PL, Rugolo M, Gasparre G, Porcelli AM. Hum Mol Genet. 2014 Mar 15;23(6):1453-66. doi: 10.1093/hmg/ddt533. Epub 2013 Oct 24.

8.Mitochondrial DNA mutation in serous ovarian cancer: implications for mitochondria-coded genes in chemoresistance.
Guerra F, Perrone AM, Kurelac I, Santini D, Ceccarelli C, Cricca M, Zamagni C, De Iaco P, Gasparre G.J Clin Oncol. 2012 Dec 20;30(36):e373-8. doi: 10.1200/JCO.2012.43.5933. Epub 2012 Nov 13.

9.A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an oncojanus function.
Gasparre G, Kurelac I, Capristo M, Iommarini L, Ghelli A, Ceccarelli C, Nicoletti G, Nanni P, De Giovanni C, Scotlandi K, Betts CM, Carelli V, Lollini PL, Romeo G, Rugolo M, Porcelli AM. Cancer Res. 2011 Oct 1;71(19):6220-9. doi: 10.1158/0008-5472.CAN-11-1042. Epub 2011 Aug 18.

10.The genetic and metabolic signature of oncocytic transformation implicates HIF1alpha destabilization.
Porcelli AM, Ghelli A, Ceccarelli C, Lang M, Cenacchi G, Capristo M, Pennisi LF, Morra I, Ciccarelli E, Melcarne A, Bartoletti-Stella A, Salfi N, Tallini G, Martinuzzi A, Carelli V, Attimonelli M, Rugolo M, Romeo G, Gasparre G. Hum Mol Genet. 2010 Mar 15;19(6):1019-32. doi: 10.1093/hmg/ddp566. Epub 2009 Dec 22.

11.Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors.
Gasparre G, Porcelli AM, Bonora E, Pennisi LF, Toller M, Iommarini L, Ghelli A, Moretti M, Betts CM, Martinelli GN, Ceroni AR, Curcio F, Carelli V, Rugolo M, Tallini G, Romeo G. Proc Natl Acad Sci U S A. 2007 May 22;104(21):9001-6. doi: 10.1073/pnas.0703056104. Epub 2007 May 15.

12.Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III.
Bonora E, Porcelli AM, Gasparre G, Biondi A, Ghelli A, Carelli V, Baracca A, Tallini G, Martinuzzi A, Lenaz G, Rugolo M, Romeo G. Cancer Res. 2006 Jun 15;66(12):6087-96. doi: 10.1158/0008-5472.CAN-06-0171.