Principal Investigators

DEO faculty is composed of 23 Principal Investigators, whose complementary expertise in the fields of cancer biology, immunology/immunotherapy, genomics, epigenomics, transcriptomics, proteomics, cell signalling, cancer models, structural biology, molecular and pharmaco-epidemiology,  cognitive and psychological science and computational biology ensures a comprehensive vision of cancer research.

Oncogenes, Transcription and Cancer

Bruno Amati

Oncogenes, Transcription and Cancer

Our research aims at a better understanding of fundamental disease mechanisms and therapeutic opportunities in MYC-driven cancers, with a particular focus on aggressive B-cell lymphomas. The MYCproto-oncogene and its product, the MYC transcription factor, have a central role in cellular growth control and oncogenesis. In normal cells, MYCis induced by growth-promoting signals, and in turn regulates genes involved in key cellular responses (growth, proliferation, apoptosis, energy metabolism, biosynthetic pathways, etc…). During tumor development, a variety of oncogenic mutations (affecting either the MYClocus, or upstream signaling pathways) can elicit deregulated MYC expression and, as a consequence, the aberrant implementation of MYC-dependent gene expression programs.MYC-driven tumors show “oncogene addiction”, indicating that MYC itself – and presumably a subset of its target genes – are required for tumor maintenance. Key questions in the field regard the mechanisms through which MYC regulates transcription, the identity of MYC-regulated genes, their function in growth control and tumorigenesis, as well as their potential as therapeutic targets. Our research addresses these questions based on a combination of advanced biological models, high-throughput “omic” approaches and computational tools. In parallel with our basic research program, we pursue translational studies aimed at the development and pre-clinical validation of innovative therapeutic strategies.

Unit of Gynecological Oncology Research

Ugo Cavallaro

Unit of Gynecological Oncology Research

Ovarian cancer (OC) remains an outstanding challenge in clinical oncology, mainly due to the lack of prevention and early diagnosis strategies and the high rate of recurrence and chemoresistance. Experimental and clinical evidence supports the hypothesis that OC relapse and drug resistance are fueled by a subpopulation of ovarian cancer stem cells (OCSC) and, hence, targeting OCSC function may lead to OC eradication. We are pursuing the identification as well as the molecular and functional characterization of OCSC, aimed at defining their biomarkers and possible therapeutic targets. Another key aspect of OC malignancy is the role of tumor microenvironment, which has emerged as a crucial player and a viable target for new therapies. In this context, the blood vessel network provides an essential support to the growth of primary tumor and metastatic implants. Such a role entails also the establishment of perivascular niches for OCSC. Our group is interested in studying novel biological mechanisms that govern OC-associated vascularization and, in particular, the crosstalk between the vasculature and OCSC. The ultimate objective is the discovery of molecular pathways that can be modulated pharmacologically in order to deprive OC of its vascular support. Our Unit is fully embedded in the IEO Gynecology Program, and we work in close collaboration with its clinical staff, which not only grants access to patient-derived samples but it also facilitates focusing on clinically relevant questions.

Endocytosis, Signalling and Cancer

Pier Paolo Di Fiore

Endocytosis, Signalling and Cancer

Our multidisciplinary laboratory hosts projects in the fields of endocytosis, stem cells and functional genomics. Over recent years, ourunderstanding of endocytosis hasevolved from that of a simple process to transport molecules across the plasma membrane, to a complex program that governs cell logistics, permitting the regulation in time and space of signalling events and of multiple cellular processes required to maintain tissue homeostasis. In accordance, many functions have been attributed to endocytic proteins that are not immediately interpretable within the classical view of endocytosis and which are related to phenotypes of upmost relevance to cancer, such as stem cell self-renewal, epithelial-to-mesenchymal transition, and migration/invasion. The overall goal of the group is to understand the different functions carried out by the endocytic cell logistics apparatus, to define its molecular workings, and to understand how its subversion contributes to tumorigenesis and the acquisition of cancer stem cell and metastatic traits. Ultimately, we aim to exploit our basic research findings to identify novel prognostic/predictive markers and therapeutic targets. Ongoing research projects aim to: Elucidate the molecular mechanisms governing endocytosis of the EGFR under physiological and pathological conditions; Characterize the functional involvement of endocytic (and related) proteins to cancer cell biology and the acquisition of cancer stem cell and metastatic traits; Characterize novel cancer markers or therapeutic targets through the identification and analysis of cancer-specific profiles; Validate novel cancer targets through translational studies.

Mucosal Immunology

Federica Facciotti

Mucosal Immunology

My research group specifically focuses on understanding and functionally manipulating for therapeutic purposes the interactions between the mucosal immune system and the intestinal microenvironment. The intestinal compartment is a complex biological system composed by different type of cells (immune cells, epithelial cells, gut microbiota) involved in functional crosstalks aimed at maintaining a balance between tolerance and immunity. These interactions may give rise to different functional outcomes. In healthy conditions immune cells contribute to intestinal homeostasis maintenance, while in genetically predisposed individuals hyperactivation of immune cells may lead to in chronic autoimmune intestinal inflammation.  In the context of intestinal tumours, defective activation of immune cells may contribute to decreased immunesurveillance and tumour development. Specifically, our projects focus at: Deciphering the role of conventional and unconventional intestinal CD4+T helper cells in contributing to tissue homeostasis and in participating to inflammatory immune responses; Understanding the functions of intestinal T lymphocytes in the control of epithelial neoplastic transformations; Dissecting the functional interactions between T cells , the gut microbiota and the intestinal microenvironment during intestinal neoplastic transformation and inflammation Manipulating the function of immune cells for therapeutic purposes. To do so, we take advantage of a translational approach involving in vitro systems, murine models of colorectal cancer and intestinal inflammation, and patients’-derived surgical specimens.

Molecular and Pharmaco-Epidemiology Unit

Sara Gandini

Molecular and Pharmaco-Epidemiology Unit

We work on primary and secondary cancer prevention projects, as well as on prognostics and predictive biomarkers of solid tumors (e.g. MC1R polymorphisms and neutrophil-to-lymphocyte ratio, Adiponectin etc.). We are interested in investigating the polygenic nature of cancer, by studying the various forms of potential interactions between genetic, phenotypic and environmental factors and their impact on both cancer development and prognosis. The advancement in technologies now allows the production of large numbers of data, generally classified as “-omics”, that need specific approach of statistical analysis. The translation of laboratory results in clinical setting is often complex and needs an integration of different information on a wide spectrum of clinical, molecular, epidemiological and lifestyle factors. We are studying the interaction between fecal and oral microbiome and biomarkers, such as vitamin D serum level, GC binding protein and VDR polymorphisms, in association with cancer risk and prognosis. Vitamin D acts on immune responses, cell cycle, and metabolic processes and there are increasing evidence on its interaction with the gut microbiota in relationship with different diseases. Our aim is to investigate the correlation between fecal and oral microbiota and vitamin D metabolism in a case-control study and a clinical trial for colorectal cancer patient to assess their role on cancer risk and outcome. We are also investigating the association between candidate single nucleotide polymorphisms (SNPS) with cancer risk, with particular attention to their direct and indirect effect in cancer risk and to gene-environment interaction. This is of particular importance for assessing preventive strategies that could be applied in a clinical context and be therefore directed to specific at risk categories basing on both genetic and clinical/epidemiological risk factors. Our group is interested in investigating the role of the minimal active dose of drug than can be used for the management of in situ disease (i.e, low dose tamoxifen for treatment of ER positive in situ neoplasia). We are also interested in studying the possibility to repurpose the large arsenal of approved, non-anticancer drugs for cancer treatment. We focus mainly on the effects of three common drugs such as metformin, beta-blockers and vitamin D. Our projects are aimed to integrate and assess the importance of epidemiological factors in translational and clinical research. With our researches, we would like to create the basis of personalized prevention and therapeutic programs for cancer that will integrate molecular, genetics and epidemiological risk factors.

Modeling and Targeting Metastatic Cancer in vivo and in vitro

Luisa Lanfrancone

Modeling and Targeting Metastatic Cancer in vivo and in vitro

The Lanfrancone Lab investigates how fundamental biological processes regulate metastasis formation and which are the driving forces beyond this phenomenon. We combine genetic and functional approaches to investigate how cancer cells react to microenvironmental cues, survive, proliferate and disseminate to distant organs. In particular, we are interested in elucidating the key molecular pathways involved in the progression from a non-invasive, locally-growing, to an aggressive, therapy-resistant metastatic tumor. Central molecular pathways converge on key cellular functions, including self-renewal, proliferation, migration and differentiation. Our hypothesis is that changes in chromatin status and metabolism can impact on the pathogenesis of cancer, as genetic alterations do, and that drug resistance can be overcome through the induction of chemo-sensitivity by inhibition of selective epigenetic and metabolic pathways and/or the use of combinatorial therapiesand drug repurposing. Our ongoing aims are: Identification of actionable candidates in therapy-resistant metastatic melanomas by in vivoand in vitroshRNA screens. Modelling of the metastatic process in vivo, to identify and target, genes and pathways involved in dissemination. Reprogramming of the metastatic phenotype. Combinatorial drug testing in vitroand in vivo. Development of a novel, multifunctional nanomedicineto target and ablate melanoma lesions.

Molecular Basis of Asymmetric Cell Divisions

Marina Mapelli

Molecular Basis of Asymmetric Cell Divisions

The connection between deregulated stem cell divisions and tumorigenesis has been one of the most important findings of the last few decades. The notion that tumours could be initiated and maintained by their own stem cells emerged in the 1970s from genetic screens, and was later stregthened by the evidence that deregulated stem cells are a major cause of relapse and resistance to traditional anticancer therapies (Santoro, EMBO Rep. 2016). In this context, we are interested in understanding the molecular mechanisms governing asymmetric stem cell divisions and fate choice, under normal and pathological conditions. To make a cell division asymmetric, the division plane needs to be tightly coordinated with cellular and polarity. This way, daughter cells are properly positioned within the tissue, inherit unequal sets of fate determinants and follow differential fates. These observations set the stage for our studies, aimed at gaining insight into the functional and organisational principles of the molecular machines orchestrating asymmetric cell divisions. To address this biological problem, we use a combination of high-resolution X-ray crystallography, cryo-Electron Microscopy, biochemical analyses on reconstituted protein complexes and stem cell biology. Our research activity is organised in three main research lines: 1) studies of complexes coordinating oriented epithelial cell divisions; 2) interplay between niche contacts and fate asymmetry, specifically for Wnt-dependent niches; and 3) implications of asymmetric divisions in cancer development, with focus on breast and intestinal cancers. We believe that gaining detailed molecular knowledge of stem cell niche-signalling and division mode will be instrumental in designing novel targeted therapies and combinatorial regimes for more effective cancer treatments.

Translational oncology

Luca Mazzarella

Translational oncology

We believe that cancer can be understood and managed only by a multi-layered approach where methods proper of multiple disciplines are integrated. These include laboratory techniques, high throughput sequencing, clinical trial design, social sciences and a heavy reliance on computational analyses. We are creating a group of enthusiastic people with variegated backgrounds to foster cross-fertilization from different branches of knowledge, to provide comprehensive answers to clinically relevant questions. We also participate in several collaborations within IEO and national and international groups. Areas of specific interest: Metabolism and cancer. We study molecular mechanisms mediating the effect of diet on cancer, with a special focus on acute myeloid leukemia and FLT3 mutations. We explore the role of polyunsaturated fatty acids in the maintenance of leukemia stem cells. Chromatin modifiers as therapeutic targets in cancer and immunity We study the role of histone modifications in hematopoietic and immune cells, and how they can be pharmacologically targeted for modulating the immune response. Sequencing-based biomarkers. We perform translational studies in clinical trials to identify biomarkers for response prediction, diagnosis and genetic risk. Bioinformatic tools for clinical genomics. We develop tools for the management of sequencing data for clinical trial design and diagnosis. Social studies applied to biomedicine, in particular on privacy and health economics.

Chromatin Alterations in Tumorigenesis

Saverio Minucci

Chromatin Alterations in Tumorigenesis

Cancer cells show global changes in chromatin structure (DNA methylation and histone post-translational modifications), that lead to stable alterations in gene expression and potentially other nuclear functions (such as DNA replication and repair). Unlike genetic lesions, those alterations are reversible since the underlying DNA sequence is unchanged: this fundamental difference between genetic and epigenetic alterations makes the epigenome much more amenable to the development of therapeutic strategies. Indeed, small molecules with the capacity to interfere with chromatin modifying enzymes have antitumor activity. The concept of epigenetic therapy has been clinically validated with the approval by regulatory authorities of a small number of drugs for use in selected forms of cancer. In our view, however, drugs interfering with epigenetic enzymes (such as DNA methyltransferases and histone deacetylases, the most advanced targets in the epigenetic arena) have been used in the vast majority of cases rather aspecifically, without taking into account the context of chromatin alterations occurring in cancer cells. We surmise therefore that one of the major goals of both basic and applied research in this area should be the search of a set of epigenetic alterations in tumor cells, that dictate sensitivity or resistance to epigenetic drugs. More recently, we have started to address also the intersection between the epigenome and tumor cell metabolism, since several metabolites control the activity of chromatin modifying enzymes.

Epigenetic Mechanisms in Cancer

Diego Pasini

Epigenetic Mechanisms in Cancer

Control of cellular identity is regulated by a complex network of autonomous and non-cell autonomous signals that converge to the nucleus and instruct each individual cell to acquire specific transcription programs to exert specific functions. The coordinated activity of DNA binding transcription factors together with a plethora of chromatin modifying and remodelling enzymes is instructed to establish specific transcription programs. These mechanisms are tightly regulated and kept under control to allow proper development and or to maintain adult tissue homeostasis. Loss of cellular identity constrains is a common feature of human tumours which frequently involves direct genetic and indirect epigenetic alterations of chromatin remodelling activities more generally defined as epigenetic factors. The central role of these activities, their enzymatic proprieties and the reduced redundancy respect to upstream signalling pathways immediately opens towards the development of novel therapeutic strategies. The work of our laboratory is focused at characterizing the molecular mechanisms underlying distinct chromatin activities under homeostatic and pathological conditions. For this, the lab takes advantage of genetic, biochemical, transcriptomic and epigenomic approaches applied to both in vivoand 3D organoids models derived from compound mice or patient samples down to a single cell level. The work in the lab has been recently focused at: Defining the role of Polycomb repressive activities in adult tissue homeostasis under physiological and pathological conditions. Dissecting the mechanistic aspects of oncogenic mutations that targets chromatin remodelling activities. Characterizing the epigenetic mechanisms underlying the development of colorectal cancer.

High Definition Disease Modelling Lab: Stem Cell and Organoid Epigenetics

Giuseppe Testa

High Definition Disease Modelling Lab: Stem Cell and Organoid Epigenetics

The accelerated generation of multiple, digitally compatible datasets across scales of cellular and organismal function is transforming biomedicine, promising unprecedented precision for prevention, diagnosis and treatment. Central to this challenge is the need to resolve the specificity, heterogeneity and dynamics of disease in physiopathologically relevant and experimentally tractable models. To this end we spearhead stem cell and organoid-based patient-specific models for human cancer and neurodevelopmental disorders, focusing on genetic and environmental causes of chromatin dysregulation as a shared and increasingly relevant layer of pathogenic mechanisms. Specifically, we start from densely phenotyped clinical cohorts and integrate multi-layered omics, single cell dynamics and high end computing to advance a foundational framework for precision oncology and neuropsychiatry. Our oncological research focuses on ovarian cancer, glioblastoma and thymomas, for which we pursue the functional dissection of the gene regulatory pathways and druggable hubs of epigenetic vulnerability that fuel tumorigenesis, metastasis or relapse. Within neurodevelopmental disorders, we study a uniquely informative panel of Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) syndromes, caused by point mutations or copy number variations in interrelated chromatin regulators and transcription factors, probing the molecular mechanisms of their convergence/distinction at single cell resolution and across multiple layers of regulation.

Istituto Europeo di Oncologia (IEO)
Istituto Europeo di Oncologia (IEO)
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