DEO faculty is composed of 22 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.
The advent of genomics in clinical practice is rapidly revolutionizing the approach to cancer prevention, diagnosis and therapy. Our objective is to translate the impressive increase in knowledge deriving from recent advances in oncogenomic research into an improvement in diagnostic and therapeutic tools. This includes both basic research projects aimed at defining mechanisms of disease and translational projects aimed at discovering new therapeutic options. Our research is developed in close collaboration with other IEO research and clinical units. In particular, our group has a long-standing interest in acute myeloid leukemia (AML). The molecular mechanisms and the genetics of AML have been thoroughly investigated, yet standard therapy regimens for most subtypes have remained unchanged in the past four decades. Despite the overall encouraging rate of complete remissions, survival rates after five years remain dismal, particularly in the elderly, which represent the majority of AML patients, and in secondary AML, therapy-related AML or other AML groups with adverse prognosis. We are tackling the unmet need of novel therapeutic options using different approaches.
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.
Nuclear Proteomics to Study Gene Expression Regulation in Cancer
We couple a strong technological attitude based on Mass Spectrometry (MS)-proteomics to the interest in nuclear signalling during cancer progression. Our innovative MS-approaches focus on two research lines: - Epi-proteomics profiling of cancer patient samples to define biomarkers for diagnosis and stratification - Analysis of cancer acetyl- and methyl-proteomes and their role in adaptive response
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.
Viruses and Cancer
The overall focus of my research lab is to determine the mechanisms by which oncogenic viruses and other tumor microenvironmental stresses contribute to neoplasia by post-translational modification (PTM) of proteins. In particular, we have been studying (i) the virus-/stress-induced SUMOylation and phosphorylation of Histone Deacetylases to show how these modifications change the neoplastic program, primarily through altering the cancer epigenome; (ii) how oncoviral proteins regulate cellular post-translational modification pathways and provide new critical signals in viral-induced carcinogenesis. As a model system, we have been studying head and neck cancers, since these tumors are both Human Papilloma Virus positive and negative. Within this context, we are currently understanding how inhibitors of cellular enzymes crucial for chromatin modification, such as Histone Deacetylases, exert anti-tumorigenesis activity, also by triggering epithelial-to-mesenchymal transition. Most recently, we have developed a keen interest in biological as well as clinical sex/gender differences in head and neck cancers.
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.
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
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
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.
Immunometabolism and Cancer Immunotherapy
Cancer immunotherapy has been one of the major breakthroughsof cancer treatments. However, despite the impressive results, the incidence of cancer is still raising and the majority of patients will receive little benefit. In the fight against cancer, CD8+T cells are the soldiers of the immune system which destroy tumor cells. However, they become progressively dysfunctional and no longer able to control tumor outgrowth. One reason for this dysfunctionality is T cells do not receive adequate fuel for their cytotoxic functions. Our research group is interested in understanding the link between T cell metabolism and immunity in cancer. Importantly, our lab focuses on understanding how this dysfunction can be reversed to harness T cells against cancer and improve immunotherapeutic treatment of cancer.
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.
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
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.
Transcriptional Control in Inflammation and Cancer
The human genome contains more than 20.000 genes whose expression must be accurately controlled in space and time, both during development and in response to external stimuli such as microbes or changes in micro-environmental conditions (e.g. hypoxia). Each cell in a tissue integrates and interprets information coming from a continuously changing micro-environment in order to properly adapt its properties and maximize its fitness. Moreover, responses to microbes or tissue damage, which are essential to restore homeostasis and eventually for organism survival, require rapid changes in gene expression whose control must be accurately tuned. Non-physiological alterations in gene expression determine abnormal cell behaviors in many diseases, including inflammatory disorders and cancer. In fact, some commonly used drugs, such as glucocorticoids, and many others currently under development, work by directly changing gene transcription or by altering chromatin properties. Our lab uses a combination of genomic, computational and functional approaches to understand molecular mechanisms that control gene expression in inflammation and cancer, with a particular focus on pancreatic cancer, a nearly invariably deadly tumor predicted to become the main cause of cancer deaths by 2030.
Microbiota and Antitumor Immunity
There is a growing appreciation of the role of the microbiota in cancer-related outcomes and, in particular, response to immunotherapy. Our lab seek for innovative strategies to improve cancer prevention and response to immunotherapy by modulating the molecular crosstalk between the microbial ecosystem, innate and adaptive immune system and their impact on tumor evolution.
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.
Biology of Glioblastomas and Brain Metastases and Potential Therapeutic Targets Unit
Our research focuses on identifying and understanding the biological mechanisms responsible for the onset of primitive and metastatic brain tumors. Our final goal is to lay the foundations for developing innovative treatments for these devastating diseases. In order to do this, we are committed in: 1. Identifying novel genetic and epigenetic traits of glioblastoma (GBM) tumor-initiating cells (TICs) explaining the mechanism of GBM occurrence and providing new opportunity of treatment. 2. Understanding of the mechanisms behind the homing of metastatic cells in brain and the development of brain metastases from breast tumors 3. Exploiting tumor organoids directly derived from brain metastases, glioblastomas and rare tumors (e.g. thymoma) to validate biological hypotheses and to test new therapeutic approaches. 4. Carrying out comprehensive molecular characterization of blood extracellular vesicles to develop a reliable liquid biopsy, leading to personalized treatment. Our aim is being able of studying tumor molecular features, predicting therapy response, following treatment efficacy and tumor recurrence through a minimally invasive blood sample. In our studies, we use a combination of patient samples, in vivomodels, next-generation sequencing, molecular and computational biology to study how brain tumors are maintained.
Pier Giuseppe Pelicci
Molecular Mechanisms of Cancer and Aging
Our group has traditionally focused on the elucidation of molecular and biological mechanisms of tumorigenesis, focusing on myeloid leukemia and breast cancer. We have i) identified and characterized several AML-associated genetic alterations (PML-RARa; NPMc+); ii) defined biological mechanisms of tumorigenesis (for example their effect on chromatin) and iii) exploited our findings for the development of novel targeted treatments (retinoic acid, HDAC inhibitors, Lysine demethylase inhibitors). Furthermore, we have defined the underlying molecular (p53 and p21) and biological (symmetric vs asymmetric division) mechanisms contributing to CSC pool maintenance. More recently, our group has been focusing on the analysis of intratumor heterogeneity, particularly on the study of adaptive responses, with the aim of defining its role during tumor progression and treatment resistance.
Genome integrity is maintained through faithful chromosome segregation at each cell division, in which one copy of a duplicated chromosome is deposited in each daughter cell. Errors in this process lead to aneuploidy, a condition in which cells carry an abnormal karyotype. Aneuploidy is the most common chromosome aberration in humans and is a widespread feature of solid tumors. To shed light on how aneuploidy contributes to tumorigenesis, it is crucial to determine how this condition impacts normal cells and to determine the immediate consequences of an imbalanced karyotype on cellular functions. Our work seeks to decipher how aneuploidy affects cell physiology by identifying and characterizing the pathways deregulated in human cells following chromosome segregation errors. To tackle this biological question, we use a combination of cell biology, molecular biology and genome editing techniques. Our goal is to expand our understanding of the biology of aneuploid cells and to identify specific features that can be targeted in cancer therapy.
Computational Cancer Biology Lab
We are interested how alterations of the DNA transform a healthy into a malignant cell. 10,000s of human genomes and epigenomes have been sequenced over the last years. These efforts uncovered a large number of genetic or epigenetic alterations in cancer patients. Given this large number of alterations it is difficult to tell which of those contribute to disease progression. Cancer development is a process that often takes many years. During this time cancer cells vary, compete and the fittest survive. We are studying the evolutionary principles underlying this process and try to understand how the environment modulates cancer evolution and contributes to the molecular variation between cancers from different tissues. Another focus of our lab is to understand how genes work together to create complex phenotypes such as cancer. Traditionally, genes have been studied in isolation. We develop methods using tools from network and systems biology to better understand the interplay between different alterations in cancer genomes and epigenomes. Ultimately, our goal is to understand the impact of genomic and epigenomic varition on patient phenotypes such as survival or drug response. We thereby support the development of diagnostic and personalized therapeutic approaches.
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.
How do cells correctly inherit their chromosomes? Understanding how cells inherit a correct number of chromosomes during cell division is a fundamental goal in biology. Errors in chromosome segregation result in aneuploidy, a condition in which cells have too few or too many chromosomes and which is associated with birth defects, infertility and cancer. To better understand how errors made during this process contribute to the transformation of a healthy cell into a cancerous one we investigate several aspects of cell division using yeast as a model for human cells. We take an interdisciplinary approach that combines genetic, biochemical and cell biological approaches to investigate how cells separate and segregate their chromosomes during mitosis. In particular we focus on the largely conserved cellular signals that coordinates cell cycle events in space and time to guarantee successful partitioning of the genetic material. Besides contributing to elucidate fundamental aspects of this essential biological process, our work may also contribute to the design of better strategies for preventing and treating human diseases in the long term.