I am a Researcher Technologist in the Center for Genomic Science of IIT@SEMM of the Istituto Italiano di Tecnologia since February 2012.
I am currently involved in projects aimed at defining the genomic landscape of acute myeloid leukemias (see the projects section of my profile for more details). In particular, the main goals of my studies are:
My all scientific career has been in the field of cancer research with molecular biology as major field of studies. I joined Pier Giuseppe Pelicci’s laboratory as PostDoctoral Fellow in the Department of Experimental Oncology at the European Institute of Oncology (Milan, Italy) in October 2003. My main project has been the identification of new cancer-related genes and signal transduction pathways that cooperate with PML-RAR in leukemogenesis, through an insertional mutagenesis approach and high throughput cloning and sequencing technologies. In the context of this project I have been collaborating with the laboratory of AJ Capobianco at the Wistar Institute in Philadelphia (PA, USA), where I worked, from September 2007 to April 2008, at dissecting the molecular complexes that contain the TDPOZs proteins, identified in our screening as cooperators of PML-RAR.
From July 1999 to September 2003, I moved to the United States of America for my first PostDoctoral experience, joining the laboratory of Anthony J Capobianco in the Department of Molecular Genetics, Biochemistry and Microbiology of the University of Cincinnati (Cincinnati (OH), USA). The goal of my project was the characterization of the molecular mechanisms of Notch signaling in neoplastic transformation.
From 1997 to 1999, I joined the group of Sylvie Ménard in the Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale dei Tumori (Milan, Italy), working on two projects: 1) the dissection of the role of SEL1L and TAN1 in neoplastic transformation and 2) the selection of peptides able to bind to the p185HER-2 ECD, using the phage-display library technique, with the aim of obtaining therapeutic tools to down-modulate the oncoprotein in vivo. In the context of this second project, I spent a few months in the Department of Biotechnology of the I.R.B.M. (Pomezia (Rome), Italy) in the laboratory of Paolo Monaci, well-known expert of phage-display technologies.
During my undergraduate experience, I worked for the Chair of Anatomy and Pathobiological Histology of the Department of Clinical and Biological Sciences, II Faculty of Medicine and Surgery of “Università degli Studi di Pavia” (Varese, Italy), performing an histopathological, immunohistochemical and ultrastructural study of gastric carcinomas related to Epstein-Barr Virus.
Acute Myeloid Leukaemias (AMLs) are haematological disorders characterized by the accumulation of a large number of cells, called blasts, blocked in an immature state of differentiation. As for other tumours, by xenotransplantation models it has been possible to show the existence of CSCs, called leukemia-initiating cells (LICs).However, both the frequency of LICs in the tumour bulk and their phenotype appear to be extremely heterogeneous. Indeed, LICs seem to differ in their origin and in their proliferative and self-renewal potential among the different types of AMLs. Recently, it has also been shown that each patient contains different leukemic subclones that evolve along a complex, branching multi-clonal evolution. Therefore, during the development of the disease a shift in clonal dominance can be observed in which minor clones are able to outcompete dominant clones. These data have important implications for AML treatment and cure. Indeed, AMLs remain an incurable disease with a poor long-term survival due to a high risk of relapse. This is very likely due to the inability of today’s cancer treatment in eradicating the LICs.
I will take advantage of a mouse model, the PML/RAR KI transgenic mouse, that develops leukemias near identical to the corresponding human disease in term of morphology, clinical manifestations and drug-sensitivity. The main goals of my study are:
In order to identify the LICs and perform clonal tracking during the development and progression of the disease, I will isolate leukemic blasts from tumours developed in PML/RAR KI mice and infect them with lentiviral vectors. Because lentiviruses integrate randomly in the host genome, each transduced cell and its clonal progeny will harbour a specific integration site that represent a unique molecular and traceable marker. After cloning, the viral integration sites will be sequenced by next generation sequencing (NGS). This experimental approach should allow establishing the number of clones and, as a consequence, of LICs forming the tumour bulk and the relative ratio among the several integrations and, therefore, the relative clonal contribution to tumour development. Moreover, by serial transplantation experiments, it will be possible to perform clonal tracking at each passage of transplantation.
In order to identify tumour suppressor genes and oncogenes relevant for the maintenance and/or progression of leukemia, I will perform high-throughput screening of short hairpin RNAs (shRNAs) libraries in vivo. Comparing, by NGS sequencing, the composition of the shRNAs present in the preinjection pool of cells to the one retrieved following tumour development in vivo and measuring their relative abundance will enable to define which shRNAs have been enriched and which have been depleted during tumour development. This should allow the identification of genes that could be used as new potential therapeutic targets.
The NGS data produced in all aforementioned experiments will be analysed by computational scientists at IIT@SEMM, with whom I will interact closely.
Riva L*, Ronchini C*, Bodini M, Lo-Coco F, Lavorgna S, Ottone T, Martinelli G, Iacobucci I, Tarella C, Cignetti A, Volorio S, Bernard L, Russo A, Melloni GE, Luzi L, Alcalay M, Dellino GI, Pelicci PG - "Acute promyelocityc leukemias share cooperative mutations with other myeloid-leukemia subgroups"- Blood Cancer J. 2013 Sep 13;3:e147. doi: 10.1038/bcj.2013.46.
M.V. Verga Falzacappa*, C. Ronchini*, L.B. Reavie, P.G. Pelicci - "Regulation of self-renewal in normal and cancer stem cells"- The FEBS Journal, 279 (19), 2012
A. Viale, F. De Franco, A. Orleth, V. Cambiaghi, V. Giuliani, D. Bossi, C. Ronchini, S. Ronzoni, I. Muratore, S. Monestiroli, A. Gobbi, M. Alkalay, S. Minucci, PG Pelicci– “Cell-cycle restriction limits DNA damage and mintains self-renewal of leukaemia stem cells” – Nature, 457 (7225), 2009
M.C. Alves-Guerra, C. Ronchini and A.J. Capobianco – “Mastermind-like-1 is a specific co-activator of b-catenin transcription activation and is essential for colon carcinoma cell survival” – Cancer Research , 67 (18), 2007
C. Ronchini and A.J. Capobianco – “Induction of cyclin D1 transcription and CDK2 activity by Notchic: implication for cell cycle disruption in transformation by Notchic" – Molecular and Cellular Biology, 21 (17), 2001
C. Ronchini and A.J. Capobianco - "Notchic-ER chimeras display hormone-dependent transformation, nuclear accumulation, phosphorylation and CBF1 activation" - Oncogene, 19 (34), 2000
R. Orlandi, M. Cattaneo, F. Troglio, P. Casalini, C. Ronchini, S. Ménard, I. Biunno – “ SEL1L expression decreases breast tumor cells aggressiveness in vivo and in vitro”- Cancer Research, 62, 2002
L. Urbanelli, C. Ronchini, L. Fontana, S. Mènard, R. Orlandi, P. Monaci - "Targeted gene transduction of mammalian cells expressing the HER2/neu receptor by filamentous phage" – Journal of Molecular Biology, 313, 2001
L.T. Lam, C. Ronchini, J. Norton, A.J. Capobianco, E.H. Bresnick - "Suppression of erythroid but not megakaryocytic differentiation of human K562 erythroleukemic cells by notch-1" - Journal of Biological Chemistry, 275 (26), 2000
M. Cattaneo, R. Orlandi, M. Zollo, C. Ronchini, G. Malferrari, L. Zannini,, S. Ménard, I. Biunno - “The expression of SEL1L and TAN-1 in normal and neoplastic cells” - International Journal of Biological Markers,15 (1), 2000
C. Formantici, R. Orlandi, C. Ronchini, S. Pilotti, G.N. Ranzani, S. Ménard - “Absence of microsatellite instability in breast carcinomas with both p53 and c-erbB-2 alterations” - The Journal of Pathology, 187 (4), 1999
Harry Rudney Post-doctoral award, University of Cincinnati, 2000
Journal of Cell Science travelling fellowship, 2008