EDUCATION
1997: PhD Degree in Biochemistry, University of Milan, Italy
1994: Board exam for Biologist
1992: Master Degree in Biological Sciences, Magna cum Laude, University of Milan, Italy
CAREER PATH
2011-present : Team Leader, Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT) Italy. The Center for Genomic Science has the goal to employ Next Generation Sequencing techniques to study the genetic and epigenetic etiology and pathology of genetic syndromes, with a main focus on Cancer. Here I am leading the Cancer Biology Group, a team composed by an heterogeneous mix of biologist and computational scientists, which are on a mission to unravel transcriptional and epigenetic mechanisms underlying cancer development, evolution and the emergence of therapy resistance. We use genome editing technologies and classic reverse genetics approaches to devise experimental models of cancer, both of hematological and solid tissue origin. On these, we conduct genome wide investigations to define global genome accessibility, chromatin states, transcription factors binding, RNA-pol2 dynamics and global transcriptional profiling (mRNA-seq, 4SU-seq and single-cell RNA-seq). We are also developing bio-informatic algorithms and programs to tackle and analyze NGS data with the final aim of providing affordable bioinformatics tools for bench-scientist and novel algorithms for the comprehensive and efficient deconvolution of NGS-sequencing data.
2009-2011: Staff Scientist, European Institute of Oncology, Milan Italy.
I was leading a group of three PhD students and a technician with the final objective of defining transcriptional and epigenetic mechanisms of oncogenic transcription factors (e.g. c-Myc) and tumor suppressive transcription factors (e.g. p53) in cellular and animal models by genome wide chromatin profiling (ChIP-seq, DNase-seq and other techniques) and expression profiling (RNA-seq).
2003-2009: Post-doctoral Fellow, European Institute of Oncology. PI: Dr. Bruno Amati. Here I focused on c-Myc, a transcription factor with oncogenic properties, which is frequently deregulated in cancer. In particular I used animal models to investigate intrinsic tumor suppressive responses linked to cellular senescence and a latent Myc induced DNA damage response.
1998-2003: Post-doctoral Fogarty fellowship, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, USA. PI: Dr. I.R. Kirsch. I investigated the cellular role of SIL, a gene involved in a recurrent genomic rearrangement in T-cell leukemia (T-ALL). I identified a role of SIL in the cell division, at the level of Mitotic exit.
1997-1998: Research assistant, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, USA. PI: Dr. I.R. Kirsch
1994-1997: Ph.D. student, Department of General Physiology and Biochemistry, University of Milan, Italy. PI: Prof. Mirella S. Pilone. I carried out biochemical and molecular biology studies to investigate the catalytic and kinetic mechanism of a D-aminoacid oxidase (DAAO), a flavoprotein that catalyzes the oxidative de-amination of D-aminoacids.
Processing of the genetic information contained in genomes is fundamental for proper execution of biological processes. This entails complex signalling pathways which converge on transcription factors to regulate selective regulation of transcription. We are focusing on two families of transcription factors, Myc and YAP/TAZ that are fundamental in controlling proliferation of somatic cells and stem cells, and regulate lineage specification and pluripotency. We have recently discovered an integrated regulatory network that potentiate Myc dependent transcription which is based on recruitment of YAP of regulatory elements of genes controlled by Myc. This allows the integration of growth factor signalling and mechanical/positional signals to regulate the expression of genes cell proliferation, cell growth and metabolism. We are currently investigating the transcriptional and epigenetic landscape underlying cellular dedifferentiation and reprogramming by YAP/TAZ.
Relevant publications:
Blaževitš et al., “MYC-Associated Factor MAX is a Regulator of the Circadian Clock”. Int J Mol Sci. (2020).
Wei et al., “BMP-2 Signaling and Mechanotransduction Synergize to Drive Osteogenic Differentiation via YAP/TAZ”. Adv Sci (2020).
Bisso et al., Cooperation Between MYC and β-Catenin in Liver Tumorigenesis Requires Yap/Taz”. Hepatology (2020).
Donato et al., “YAP/TAZ role in physiological and malignant hematopoiesis”, Leukemia (2018).
de Pretis et al., “Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation”. Genome Res. (2017).
Croci et al.,“Transcriptional integration of mitogenic and mechanical signals by Myc and YAP”. Genes Dev (2017).
Oncogenes highjack normal cells to impair their differentiation programs and promote their limitless and deranged proliferation. This may create intrinsic liabilities that can be exploited to design targeted therapies. In our recent studies, we have identified genome stability as an Achilles’ heel in Myc driven cancer. We are conducting genetic screens to identify and characterize genes that are selectively required by cancer cells to prevent rampant genome destabilization. We have identified a number of genes that are required to prevent replicative stress (i.e. massive DNA damage that develops during DNA replication) and we are currently focusing on their characterization, to unravel their mechanism of action. In parallel, we are actively pursuing their characterization as potential therapeutic targets in preclinical studies.
Relevant publications:
Rohban et al., “The cohesin complex prevents Myc-induced replication stress” Cell Death Dis. 2017
Donato et al., “Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven tumors”. Leukemia (2016).
Rohban and Campaner “Myc induced replicative stress response: How to cope with it and exploit it. Biochim Biophys Acta. (2015).
Murga et al., “Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors”. Nat Struct Mol Biol. (2011).
YAP and TAZ are two transcriptional co-activators originally identified as regulated by the Hippo pathway and later recognized as key effectors of cytoskeletal tension, cell polarity, cell-to-cell contacts and G-protein coupled receptors. As such, YAP/TAZ are emerging as essential genes that are able to integrate chemical and mechanical signals in order to regulate tissue growth during development, regeneration and cancer. In several cancer types, YAP/TAZ activity has been linked to mesenchymal-like features, metastatic potential, chemoresistance and cancer stem cell properties. In particular, TAZ is a prominent master regulator of such activities in basal-like breast cancers. Indeed, expression data indicated a marked enrichment for TAZ gene signatures in breast cancers (BCs), with strong association with high histological grade, stem cell signatures and metastasis typical of the basal-like BC subtype. Coherently, TAZ is overexpressed in this sub-set of tumors, both at the mRNA and protein level, with a concomitant strong nuclear localization, which is prognostic of poor clinical outcome. Loss of function studies showed that its silencing strongly reduced the number of stem cells both in BC cell lines and in primary human BCs, and impaired metastasis of primary BC cells. On the other hand, gain of function genetics suggested that TAZ activation augmented cancer stem cells (CSCs) and tumor initiating cells (TICs) in low grade breast cancers and increased their metastatic potential. Thus, TAZ plays a prominent causal role in BC progression, promoting the acquisition of CSC features, malignancy, metastatic relapse and therapy resistance. While activation of YAP/TAZ is emerging as a hallmark of aggressive tumors, the underlying genetics of their deregulation is less clear, given the low rate of mutations of their known upstream regulators. This suggests that deregulation of other genes, yet to be discovered is responsible for YAP/TAZ activation in cancer cells. To address this, we have performed a loss of function genetic screen, which has allowed the identification of a number of novel regulators. We are currently performing molecular and cellular characterization of selected genes in order to define their mechanism of action and their relevance in YAP/TAZ regulation. In parallel, we are conducting CRISPR/CAS9 genetic screens in tumors, in order to address their role in cancer progression, cancer stem cells properties, in-vivo cancer cell dissemination and chemo-resistance.
The advent of next generation sequencing technologies has offered the possibilities to ask and address biological questions related to genome regulation and structure to an unprecedented level. This requires the ability to develop sophisticated bio-informatic tools able to analyze high density quantitative data over the genome landscape, in order to perform multiscale analysis. We are developing command line tools and web-based graphical interfaces to allow smooth analysis of complex data by the broad community of life scientists involved in genomic studies based on NGS applications (Illumina), Single Molecule sequencing (Nanopore) and Single-cell analysis (10xGenomics).
Relevant publications:
Ceddia et al., “Association rule mining to identify transcription factor interactions in genomic regions”. Bioinformatics (2020).
Bianchi et al., “Integrated Systems for NGS Data Management and Analysis: Open Issues and Available Solutions”. Front Genet.(2016).
Keystone Symposia scholarship, travel Award funded by the International Society of Differentiation (2008)
Fogarty Post-doctoral Fellowship, the National Institute of Health (NIH), Bethesda, USA. (1998-2003)
Recipient of the 2002 Fellow Award for Research Excellence at the National Institute of Health (NIH), Bethesda, USA.
PHARMACEUTICAL COMPOSITION AND METHOD FOR REGULATING ABNORMAL CELLULAR PROLIFERATION, PCT Patent Application No. PCT IL2006-001324.
L’Istituto Italiano di Tecnologia (IIT) è una fondazione di diritto privato - cfr. determinazione Corte dei Conti 23/2015 “IIT è una fondazione da inquadrare fra gli organismi di diritto pubblico con la scelta di un modello di organizzazione di diritto privato per rispondere all’esigenza di assicurare procedure più snelle nella selezione non solo nell’ambito nazionale dei collaboratori, scienziati e ricercatori ”.
IIT è sotto la vigilanza del Ministero dell'Istruzione, dell'Università e della Ricerca e del Ministero dell'Economia e delle Finanze ed è stato istituito con la Legge 326/2003. La Fondazione ha l'obiettivo di promuovere l'eccellenza nella ricerca di base e in quella applicata e di favorire lo sviluppo del sistema economico nazionale. La costruzione dei laboratori iniziata nel 2006 si è conclusa nel 2009.
Lo staff complessivo di IIT conta circa 1440 persone. L’area scientifica è rappresentata da circa l’85% del personale. Il 45% dei ricercatori proviene dall’estero: di questi, il 29% è costituito da stranieri provenienti da oltre 50 Paesi e il 16% da italiani rientrati. Oggi il personale scientifico è composto da circa 60 principal investigators, circa 110 ricercatori e tecnologi di staff, circa 350 post doc, circa 500 studenti di dottorato e borsisti, circa 130 tecnici. Oltre 330 posti su 1400 creati su fondi esterni. Età media 34 anni. 41% donne / 59 % uomini.
Nel 2015 IIT ha ricevuto finanziamenti pubblici per circa 96 milioni di euro (80% del budget), conseguendo fondi esterni per 22 milioni di euro (20% budget) provenienti da 18 progetti europei, 17 finanziamenti da istituzioni nazionali e internazionali, circa 60 progetti industriali
La produzione di IIT ad oggi vanta circa 6990 pubblicazioni, oltre 130 finanziamenti Europei e 11 ERC, più di 350 domande di brevetto attive, oltre 12 start up costituite e altrettante in fase di lancio. Dal 2009 l’attività scientifica è stata ulteriormente rafforzata con la creazione di dieci centri di ricerca nel territorio nazionale (a Torino, Milano, Trento, Parma, Roma, Pisa, Napoli, Lecce, Ferrara) e internazionale (MIT ed Harvard negli USA) che, unitamente al Laboratorio Centrale di Genova, sviluppano i programmi di ricerca del piano scientifico 2015-2017.
Istituto Italiano di Tecnologia (IIT) is a public research institute that adopts the organizational model of a private law foundation. IIT is overseen by Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero dell'Economia e delle Finanze (the Italian Ministries of Education, Economy and Finance). The Institute was set up according to Italian law 326/2003 with the objective of promoting excellence in basic and applied research andfostering Italy’s economic development. Construction of the Laboratories started in 2006 and finished in 2009.
IIT has an overall staff of about 1,440 people. The scientific staff covers about 85% of the total. Out of 45% of researchers coming from abroad 29% are foreigners coming from more than 50 countries and 16% are returned Italians. The scientific staff currently consists of approximately 60 Principal Investigators, 110 researchers and technologists, 350 post-docs and 500 PhD students and grant holders and 130 technicians. External funding has allowed the creation of more than 330 positions . The average age is 34 and the gender balance proportion is 41% female against 59% male.
In 2015 IIT received 96 million euros in public funding (accounting for 80% of its budget) and obtained 22 million euros in external funding (accounting for 20% of its budget). External funding comes from 18 European Projects, other 17 national and international competitive projects and approximately 60 industrial projects.
So far IIT accounts for: about 6990 publications, more than 130 European grants and 11 ERC grants, more than 350 patents or patent applications, 12 up start-ups and as many which are about to be launched. The Institute’s scientific activity has been further strengthened since 2009 with the establishment of 11 research nodes throughout Italy (Torino, Milano, Trento, Parma, Roma, Pisa, Napoli, Lecce, Ferrara) and abroad (MIT and Harvard University, USA), which, along with the Genoa-based Central Lab, implement the research programs included in the 2015-2017 Strategic Plan.
