Group on Functional Genetics and Mitochondrial Metabolism of Solid Tumours

Research areas:

The Functional Genetics and Mitochondrial Metabolism of Solid Tumours Group is a multidisciplinary team that combines expertise in genetics, biochemistry and cellular and molecular biology to study the role of mitochondria and their DNA in the progression of solid neoplasms, with a particular focus on ovarian cancer, in collaboration with the gynaecological cancer surgery, physical chemistry and plasma engineering groups.

The research activities focus on the analysis of the molecular mechanisms contributing to the onset of indolent tumour phenotypes, with a non-conventional approach that stems from the Group's previous studies on the modifying role of mitochondrial mutations and the lack of Complex I in the mitochondrial respiratory chain. The results obtained led to the definition of oncogene as a gene that, when mutated, reduces tumour progression. Furthermore, these results led to the development of lines of research concerning the use of Complex I inhibitors as adjuvants in therapeutic protocols.

Through studies on animal models and on 3D human models in bioreactors and using techniques ranging from molecular genetics to biochemistry, from cell biology to mass spectrometry, the group is focused on identifying adaptive mechanisms, both cell-autonomous and non-cell-autonomous, following treatment with conventional chemotherapeutics at various stages of tumorigenesis. In particular, hypoxia response, metabolic adaptation, tumour neo-angiogenesis and tumour-microenvironment cross-talk are the main topics of interest of the group.

Title of research projects carried out at the CRBA

Search for metabolic targets and inhibition of mitochondrial complex I for the conversion of carcinomas into benign oncocytomas
Defining the potential of circulating tumour cells as diagnostic and prognostic markers in ovarian cancer patients.
Screening of compounds on HIF1a stabilisation and regulation of tumourigenic potential

PUBLICATIONS

Leggi dettagli

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.

responsibles

Anna Maria Porcelli

Full Professor

Department of Pharmacy and Biotechnology

+39 051 20 9 1282

Group on Functional Genetics and Mitochondrial Metabolism of Solid Tumours

Research areas:

Title of research projects carried out at the CRBA

PUBLICATIONS

responsibles

Anna Maria Porcelli

Giuseppe Gasparre

team

Anna Maria Ghelli

Luisa Iommarini

Ivana Kurelac

Monica De Luise

Manuela Sollazzo

Camelia Coada

Stefano Miglietta

Gaia Tioli

Ottavia Tartagni

Luigi D'Angelo

Sara Milioni

Beatrice Cavina

Iacopo Gherardi

Laura Lanteri

Francesca Nanetti