Identification, characterization and targetability of novel cancer-associated genes and pathways
Cancer is the major life threatening disease of our time. Despite improvement in patient therapy, most cancers remain incurable, urging the need to define more efficient therapeutic approaches. In our lab we plan to establish novel cancer-associated proteins and pathways, with the aim of discovering new druggable targets.
Currently, we are primarily focused on dissecting the role of the novel onco-suppressor complex FAM46C/FNDC3A.
The FAM46C/FNDC3A complex was originally found frequently inactivated in multiple myeloma (MM) and, for this reason, was initially characterized solely in this specific malignancy. In MM cells, the FAM46C/FNDC3A complex regulates intracellular vesicle trafficking by localizing at the endoplasmic reticulum. Specifically, by diverting lysosomes towards exocytosis, the complex: 1) negatively affects autophagy and 2) alters protein secretion. Defective autophagy causes faulty misfolded protein clearing, an event which in turn causes accumulation of protein aggregates and consequent apoptosis induction, while altered protein secretion affects the tumour microenvironment, as the secretome of FAM46C-expressing cells is capable to inhibit the differentiation of T regulatory cells (Tregs), a class of T cells which is important to inhibit anti-tumour immune responses.
At present, in the lab we are better defining both the cell-autonomous and non-cell-autonomous effects exerted by a functional FAM46C/FNDC3A complex and, since FAM46C was proposed to behave as a pan-cancer tumour suppressor, we are expanding our analyses to different tumours setups.
Starting from the seminal observation that, among CD4+ T cell subsets, FAM46C is expressed at really high levels only in Tregs, we are also exploring its involvement in both Treg differentiation and proper suppressor capacity.
Given the fact that FAM46C is part of a protein family composed by three other members, namely FAM46A, B and D, we plan, in the near future, to extend our research also on other FAM46 family members.
Moreover, by exploring novel approaches based on datamining of omics data, we plan to define, validate and investigate on novel cancer-specific or broad cancer oncodrivers/tumour suppressors, with our final aim always being the discovery of new targettable proteins/pathway.
Projects
- Dissecting the function and druggability of the intracellular networks regulated by the FAM46C oncosuppressor complex.
- Defining the role of FAM46C in Treg functionality.
- Unraveling the controversial role of FAM46C in antiviral responses.
- Mapping altered pathways in cancer using novel datamining approaches.
Team
| Nome / Name | Ruolo / Role | |
|---|---|---|
| Giancarlo Lai | Pre-doctoral fellow | lai@ingm.org |
| Federica De Grossi | Student | degrossi@ingm.org |
Pubblicazioni
Marilena Mancino, Giancarlo Lai, Federica De Grossi, Alessandro Cuomo, Lara Manganaro, Giacomo M Butta, Ivan Ferrari, Elisa Vicenzi, Guido Poli, Elisa Pesce, Stefania Oliveto, Stefano Biffo*, Nicola Manfrini*. FAM46C Is an Interferon-Stimulated Gene That Inhibits Lentiviral Particle Production by Modulating Autophagy. Microbiol Spectr. 2023 Jun 26:e0521122. doi: 10.1128/spectrum.05211-22.
* Corresponding authors.
Maria Kiratzis, Giancarlo Lai, Piera Calamita, Marilena Mancino, Marcello Iriti, Nicola Manfrini and Simone Gallo. RACK1 release from the Ribosome Couples Translational Regulation with Starving Signaling and Possibly Depends on Phosphorylation of Key Serine and Threonine Residues. Cell Mol Biol (Noisy-le-grand). 2023 Jan 31;69(1):7-12. doi: 10.14715/cmb/2022.69.1.2.
Annarita Miluzio, Alessandro Cuomo, Chiara Cordiglieri, Lorena Donnici, Elisa Pesce, Mauro Bombaci, Matteo Conti, Alessandra Fasciani, Luigi Terracciano, Lara Manganaro, Mirco Toccafondi, Alessandra Scagliola, Stefania Oliveto, Sara Ricciardi, Renata Grifantini, Raffaele De Francesco, Sergio Abrignani, Nicola Manfrini* and Stefano Biffo*. Mapping of functional SARS-CoV-2 receptors in human lungs establishes differences in variant binding and SLC1A5 as a viral entry modulator of hACE2. Ebiomedicine. 2022 Dec 28;87:104390 doi: 10.1016/j.ebiom.2022.104390. * Corresponding authors.
Alessandra Scagliola, Annarita Miluzio, Giada Mori, Sara Ricciardi, Stefania Oliveto, Nicola Manfrini and Stefano Biffo. Inhibition of eIF6 Activity Reduces Hepatocellular Carcinoma Growth: An In Vivo and In Vitro Study. Int J Mol Sci. 2022 Jul 13;23(14):7720. doi: 10.3390/ijms23147720.
Elisa Pesce*, Nicola Manfrini*, Chiara Cordiglieri, Spartaco Santi, Alessandra Bandera, Andrea Gobbini, Paola Gruarin, Andrea Favalli, Mauro Bombaci, Alessandro Cuomo, Federica Collino, Giulia Cricrì, Riccardo Ungaro, Andrea Lombardi, Davide Mangioni, Antonio Muscatello, Stefano Aliberti, Francesco Blasi, Andrea Gori, Sergio Abrignani, Raffaele De Francesco, Stefano Biffo, Renata Grifantini. Exosomes Recovered From the Plasma of COVID-19 Patients Expose SARS-CoV-2 Spike-Derived Fragments and Contribute to the Adaptive Immune Response. Frontiers in Immunology. 2022. 12:785941. doi: 10.3389/fimmu.2021.785941. * The two authors contributed equally to the work.
Arta Ajazi , Christopher Bruhn , Ghadeer Shubassi , Chiara Lucca , Elisa Ferrari , Angela Cattaneo , Angela Bachi , Nicola Manfrini , Stefano Biffo, Emanuele Martini , Saverio Minucci , Claudio Vernieri , Marco Foiani. Endosomal trafficking and DNA damage checkpoint kinases dictate survival to replication stress by regulating amino acid uptake and protein synthesis. Dev Cell. 2021 Sep 27;56(18):2607-2622.e6. doi: 10.1016/j.devcel.2021.08.019.
Alessandra Scagliola, Annarita Miluzio, Gabriele Ventura, Chiara Cordiglieri, Stefania Oliveto, Nicola Manfrini, Delia Cirino, Luca Valenti, Guido Baselli, Roberta D’Ambrosio, Marco Maggioni, Daniela Brina, Alberto Bresciani and Stefano Biffo. Targeting of Translation Induces a Metabolic Rewiring that Reduces NAFLD and Prevents Activation of Carcinogenesis. Nature Communications. 2021. 12, 4878 (2021). https://doi.org/10.1038/s41467-021-25195-1.
Nicola Manfrini, Marilena Mancino, Matteo Balestra, Annarita Miluzio, Stefania Oliveto, Matteo Balestra, Piera Calamita, Roberta Alfieri, Riccardo L. Rossi, Marco Sassoè-Pognetto, Chiara Salio, Alessandro Cuomo, Tiziana Bonaldi, Marcello Manfredi, Emilio Marengo, Elia Ranzato, Simona Martinotti, Davide Cittaro, Giovanni Tonon and Stefano Biffo. FAM46C and FNDC3A are multiple myeloma tumor suppressors that act in concert and impair clearing of protein aggregates and autophagy. Cancer Research, 2020, 80(21):4693-4706. doi: 10.1158/0008-5472.CAN-20-1357.
Nicola Manfrini, Sara Ricciardi, Paola Gruarin, Roberta Alfieri,Gabriele Ventura, Piera Calamita, Andrea Favalli, Massimiliano Pagani and Stefano Biffo. Ribosome profiling unveils translational regulation of metabolic enzymes in primary CD4 + Th1 cells. Dev. Comp. Immunol. 2020. Aug; 109:103697.doi:10.1016/j.dci.2020.103697.
Elisa Pesce, Annarita Miluzio, Lorenzo Turcano, Claudia Minici 3, Delia Cirino, Piera Calamita, Nicola Manfrini, Stefania Oliveto, Sara Ricciardi, Renata Grifantini, Massimo Degano, Alberto Bresciani and Stefano Biffo. Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits. Cells 2020, 9(1), 172; https://doi.org/10.3390/cells9010172
Nicla Romano, Matteo Veronese, Nicola Manfrini, Lello Zolla and Marcello Ceci. Ribosomal RACK1 promotes proliferation of neuroblastoma cells independently of global translation upregulation. Cell Signal. 2018 Oct 1;53:102-110.
Simone Gallo, Sara Ricciardi, Nicola Manfrini, Elisa Pesce, Stefania Oliveto, Piera Calamita, Marilena Mancino, Elisa Maffioli, Monica Moro, Mariacristina Crosti, Valeria Berno, Mauro Bombaci, Gabriella Tedeschi, Stefano Biffo. RACK1 Specifically Regulates Translation through Its Binding to Ribosomes. Mol Cell Biol. 2018 Sep 10. pii: MCB.00230-18.
Sara Ricciardi*, Nicola Manfrini*, Roberta Alfieri, Piera Calamita, Maria Cristina Crosti, Rolf Müller, Massimiliano Pagani, Sergio Abrignani and Stefano Biffo.The translational machinery of human CD4+ T cells is poised for activation and controls the switch from quiescence to metabolic remodelling. Cell Metab. 2018 Sep 6. pii: S1550 4131(18)30510-2. * The two authors contributed equally to the work.
Stefano Biffo, Nicola Manfrini and Sara Ricciardi. Crosstalks between translation and metabolism in cancer. Curr Opin Genet Dev. 2017 Nov 15;48:7581
Nicola Manfrini*, Sara Ricciardi, Annarita Miluzio, Maya Fedeli, Alessandra Scagliola, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis and Stefano Biffo. Data on the effects of eIF6 downmodulation on the proportions of innate and adaptive immune system cell subpopulations and on thymocyte maturation Data Brief. 2017 Aug 30;14:653-658. * Corresponding author.
Nicola Manfrini*, Sara Ricciardi, Annarita Miluzio, Maya Fedeli, Alessandra Scagliola, Daniela Brina, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis and Stefano Biffo. High levels of eukaryotic Initiation Factor 6 (eIF6) are required for immune system homeostasis and for steering the glycolytic flux of TCR stimulated CD4+ T cells in both mice and humans. Dev Comp Immunol. 2017 Jul 22;77:69-76. * Corresponding author.
Stefania Oliveto, Marilena Mancino, Nicola Manfrini and Stefano Biffo. Role of microRNAs in translation regulation and cancer. World J Biol
Chem. 2017 Feb 26;8(1):45-56
Annarita Miluzio, Sara Ricciardi, Nicola Manfrini, Roberta Alfieri, Stefania Oliveto, Daniela Brina, Stefano Biffo. Translational control by mTOR-independent routes: how eIF6 organizes metabolism. Biochem Soc Trans. 2016 Dec 15;44(6):1667-1673.
Simone Gallo and Nicola Manfrini*. Working hard at the nexus between cell signaling and the ribosomal machinery: An insight into the roles of RACK1 in translational regulation. Translation (Austin). 2015 Nov 23;3(2):e1120382. * Corresponding Author.
Nicola Manfrini, Michela Clerici, Maxime Wery, Cristina Vittoria Colombo, Marc Descrimes, Antonin Morillon, Fabrizio d’Adda di Fagagna and Maria Pia Longhese. Resection is responsible for loss of transcription around a double-strand break in Saccharomyces cerevisiae. Elife. 2015 Jul 31;4. doi: 10.7554/eLife.08942.
Nicola Manfrini, Camilla Trovesi, Maxime Wery, Marina Martina, Daniele Cesena, Marc Descrimes, Antonin Morillon, Fabrizio d’Adda di Fagagna and Maria Pia Longhese. RNA processing proteins regulate Mec1/ATR activation by promoting generation of RPA coated ssDNA . EMBO Rep 2015. Feb;16(2):221-31.
Camilla Trovesi*, Nicola Manfrini*, Marco Falcettoni and Maria Pia Longhese. Cell cycle-dependent regulation of the DNA damage response. J Mol Biol. 2013 Nov 29;425(23):4756-66. * the two authors contributed equally to the work.
Nicola Manfrini, Elisa Gobbini, Veronica Baldo, Giovanna Lucchini and Maria Pia Longhese. G(1)/S and G(2)/M cyclin-dependent kinase activities commit cells to death in the absence of the S-phase checkpoint. Mol Cell Biol. 2012. Dec;32(24):4971-85.
Diego Bonetti, Michela Clerici, Nicola Manfrini, Giovanna Lucchini and Maria Pia Longhese. The MRX complex plays multiple functions in resection of Yku- and Rif2-protected DNA ends. PLoS One. 2010 Nov 30;5(11):e14142.
Maria Pia Longhese, Diego Bonetti, Nicola Manfrini and Michela Clerici. Mechanisms and regulation of DNA end resection. EMBO J. 2010 Sep 1;29(17):2864-74.
Nicola Manfrini, Ilaria Guerini, Andrea Citterio, Giovanna Lucchini, and Maria Pia Longhese. Processing of Meiotic DNA Double Strand Breaks requires Cyclin dependent Kinase and Multiple Nucleases. J Biol. Chem. 2010 Apr 9;285(15):11628-37.
Maria Pia Longhese, Diego Bonetti, Ilaria Guerini, Nicola Manfrini and Michela Clerici. DNA double-strand breaks in meiosis: Checking their formation, processing and repair. DNA Repair (Amst). 2009 Sep 2;8(9):1127-38.
Hugo Cartagena-Lirola, Ilaria Guerini, Nicola Manfrini, Giovanna Lucchini and Maria Pia Longhese. Rad53 checkpoint kinase contributes to monitor the integrity of meiotic chromosomes in S. cerevisiae. Mol Cell Biol. 2008 Jul;28(14):4480-93.
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