Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia Istituto di Ricovero e Cura a Carattere Scientifico. Scientific Report 2013

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1 Candiolo Cancer Institute Fondazione del Piemonte per l Oncologia Istituto di Ricovero e Cura a Carattere Scientifico Scientific Report 2013

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3 Candiolo Cancer Institute Contents About Us 5 The Link with the University of Torino 7 Mission 9 Research Synopsis 11 Mechanisms of Cancer Onset and Progression 13 From Molecular Biology to Precision Medicine 23 Investigational Clinical Oncology 35 Applied Clinical Research 39 Clinical Services 55 Grant Office and Research Administration 57 Core Facilities 58 List of Publications 61 3

4 Paolo M.Comoglio MD, Scientific Director - James Dewey Watson, Nobel laureate (lecturing at the institute) - Allegra Agnelli, President of the Fondazione Piemontese per la Ricerca sul Cancro - Giampiero Gabotto, Managing Director of Fondazione del Piemonte per l Oncologia 4 About Us

5 THE CANDIOLO CANCER INSTITUTE Candiolo Cancer Institute is a private non-profit institution founded and supported by the Fondazione Piemontese per la Ricerca sul Cancro-Onlus (FPRC) and operated by the Fondazione del Piemonte per l Oncologia (FPO: a joint venture between the FPRC and the Regione Piemonte). It is linked to the University of Torino Medical School. Its mission is a significant contribution to fight cancer, by understanding the basics, and by providing state-of-the-art diagnostic and therapeutic services. At the core of the Institute is the interface between molecular biology and medicine. The FPRC provides enduring fund raising to complete and develop the Institute s buildings and technologies to foster research. CANDIOLO CANCER INSTITUTE About Us 5

6 6 The Link with the University of Torino

7 THE LINK WITH THE UNIVERSITY OF TORINO Since its founding, The Candiolo Cancer Institute has been linked to the University of Torino by formal agreements, the first one contracted in 1994, two years before the completion of the buildings. The cooperation between the Institute and the University was renewed and implemented by a series of agreements signed in the 2002 and in the 2011, to share scientific programs of advanced oncological research. To date, in the Institute operates a branch of the Department of Oncology, born in 2012, and host a number of investigators scattered among other department of the University or the Politecnico of Turin. The University Department of Oncology gathers academic competences in the field of Cancer research, both basic and clinical. The Department belongs to the School of Medicine and its personnel has teaching responsibilities in academic courses. Students and graduates (PhD and MD) are offered specialized and meticulous formative programs, in a multidisciplinary environment in house, at pre- and post-doctoral level, aimed at the underpinning of creative, independent and productive researchers in the cancer field. Embedded in the Candiolo Cancer Institute, the University of Torino has 19 full or associate professors, 8 technicians, 3 clerks and 66 young researchers, working full-time. The Link with the University of Torino 7

8 8 Mission

9 MISSION Candiolo Cancer Institute is a biomedical and clinical research center entirely devoted to the study and the treatment of cancer. Its mission is to transfer experimental preclinical information into clinical practice, through the continuous flow of knowledge from the fields of genetics, molecular and cell biology, pathology. The Institute aims to offer a significant contribution to the defeat of the disease through scientific research and clinical practice of excellence. In order to fulfill these goals, the Institute: (i) capitalizes on knowledge by conducting scientific research in oncology and at the same time promoting a fast transfer of knowledge to the clinical practice; (ii) provides assistance in cancer prevention, including the identification of genetic risk factors; (iii) performs diagnostic studies, using state-of-the-art instrumentation and technology; (iv) provides a full cycle of treatment on the premises, employing -besides the best conventional therapies protocols for novel targeted therapies and clinical trials for precision medicine. Focus Basic and clinical research makes the Institute of Candiolo a center of excellence focussed in the study, prevention and treatment of the dreadful complication of cancer, metastasis. Basic Research The current knowledge about the mechanisms of cancer onset and progression is provided by basic disciplines, such as genetics, cell and developmental biology. Thanks to these studies, it is possible to classify tumors not only on the basis of their site of origin and histopathological features, but, notably, by the identification of the genetic lesion(s) that support their growth. The tasks of the Institute basic research are aimed at understanding the mechanisms that control normal cell functions responsible for proliferation, and at analyzing how these mechanisms are corrupted during neoplastic transformation. The topics include signal transduction, DNA duplication, cell division, differentiation, senescence, apoptosis and cell motility. Recent studies suggest that anti-neoplastic therapy is really effective not only when it hits the appropriate molecular target (vide infra), but especially when hits the cells feeding the tumor mass. Indeed, most of the cells of the neoplastic mass are quite innocuous and can be attacked with classic therapies, while only a small fraction of them are resistant to treatment and able to regenerate the tumor. This small subpopulation includes the cancer stem cells strictly related to normal stem cells which control the development of our organism during embryonic life and allow us to renew the worn parts in adult life. The up-to-date conceptualization of Cancer defines it as a somatic, genetic disease of the stem cells. Translational Research (ECMO: Experimental Clinical Molecular Oncology) Translational research is the heart of the Institute, bridging the gap between basic and clinical research. Based on recent technological advances, genomic analysis makes possible in a significant percentage of cases the identification of genetic alteration(s) with a driver role in tumor development. However, the contribution of each lesion to the transformed phenotype remains elusive. Moreover, knowledge is still insufficient about the mechanisms that control the lack of response to targeted therapies, even in the presence of the molecular target (primary resistance), as well as on the mechanisms that lead to progressive attenuation of the response after prolonged treatment (acquired resistance). Mission 9

10 ECMO research aims at the fulfillment of some ambitious Goals to integrate the traditional prognostic and diagnostic factors with a detailed characterization of the genetic and functional alterations of the tumor; to identify new malfunctioning regulatory pathways in cancer; to isolate and study the cancer stem cells; to develop new preclinical platforms that can reliably disclose and understand in detail the prospective results of clinical practice. The generation of this kind of knowledge is necessary to designt clinical trials that will be no longer based on empirical observations but on a strong rational. Investigational Clinical Oncology (INCO) Cancer is a complex disease, tied to genetic lesions, that increase in number over time, as a consequence of genetic instability and exposure to environmental carcinogens. Thus, a cell clone proliferates and invades the adjacent tissues in uncontrolled way. Since cancer cells contain several genetic anomalies, and tend to accumulate more anomalies as time passes, cancer is a heterogeneous and hard-to-attack disease, just because it would be necessary to aim at many targets that continuously change. The molecular lesions that cause and sustain the most tumors are, however, finite in number (the bona fide oncogenes). These findings drove clinical pharmacology to commit to an epochal effort to create drugs, called targeted, able to contrast the function of specific oncogenes. The strategy of the Institute at Candiolo intends to make significant contributions to the field of cancer targeted therapy by: (i) identifying pathologies and recruiting patients sensitive to the therapies currently in use; (ii) planning and performing in international networks the related clinical trials; (iii) developing translational and preclinical research aimed at designing new targeted therapies, if not available yet. Molecular diagnosis and personalized medicine The success of targeted therapies is based on the rationale that the target molecule is druggable as a consequence of the genetic anomaly in the tumor but not in the healthy tissue, and therefore its deactivation has consequences restricted to the neoplastic mass, with a minimum of off-target consequences, leading to generic organ damage. This notion has two important clinical outcomes: first of all, before treating patients with a given targeted therapy, it is necessary to verify the presence of the genetic lesion predictive of the sensitivity to the drug. Second in the perspective of targeted therapies the tumors will be classified not only according to their site of origin and/or morphological features, but also on the molecular lesion(s) which earmarks them and, at the same time, makes them vulnerable to a targeted treatment. Therefore, new therapies are not only targeted but also personalized. This new approach is called precision medicine. Clinical Research At the Institute, oncologists, surgeons and radiotherapists cooperate with scientists to design clinical trials based on molecular data, intended to verify hypotheses and generate novel ones. In order to make this cooperation productive, the Institute manages a daily net of interactions involving formal aspects (seminars and meetings), training (refresher courses and lessons), operational efforts (contacts with the pharmaceutical companies, and management of regulatory instruments). Clinical Research is the last and more direct haven to improve the assistance to cancer patients, providing them with the most appropriate, novel, safe and effective therapeutic approach, according to the genetic characteristic of their own tumor, as an ultimate means to increase their life expectancy. Paolo M.Comoglio MD (Scientific Director) 10 Mission

11 RESEARCH SYNOPSIS Topic 1: The mechanisms of onset and progression of cancer 1.1 Role of Semaphorins in invasion, metastasis and angiogenesis 1.2 The plasma membrane in cell migration and invasiveness 1.3 Tumor angiogenesis Topic 2: From Molecular Biology to Precision Medicine 2.1 Oncogenes and growth factors 2.2 Genetics of the response to anti-cancer therapy 2.3 Preclinical models of personalized therapies 2.4 Resistance to targeted therapy Topic 3: Investigative clinical research: rationale for the planning of clinical trias 3.1 HERACLES e ARES: Precision medicine trials for metastatic colon carcinoma 3.2 HERLAP: Personalized treatment of mammary carcinoma 3.3 AGNOSTOS: Therapy of metastatic cancers from unknown primary origin Topic 4: Applied clinical research 4.1 Pathology of colorectal cancer onset and progression 4.2 Implementation of current therapeutic strategies 4.3 Novel approaches to surgical oncology 4.4 Radiotherapy, imaging and laboratory medicine Research Synopsis 11

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13 Research Topic 1: Mechanisms of cancer onset and progression. The current knowledge on mechanisms of cancer onset and progression has been provided by basic disciplines, such as cell biology, developmental biology and genetics. The tasks of Research Topic 1 are aimed at understanding the mechanisms controlling the normal cell functions responsible for the regulation of cell proliferation and at analyzing how these mechanisms are corrupted during neoplastic transformation. The topics include signal transduction, DNA duplication and cell division processes, differentiation, senescence, apoptosis and cell invasion. Special attention is given to the microenvironment and to the relations of the neoplastic cell with the adjacent cells. In the past, the angiogenic process and the vascularization of the tumor mass have been studied in detail. Research Topic 1 is focussed on: 1.1 The role of Semaphorines in invasiveness, metastases and angiogenesis 1.2 The plasma membrane in metastases dissemination 1.3 Tumor angiogenesis MET gene amplification and MET Protein overexpression in a Human gastric carcinoma The mechanisms of cancer onset and progression 13

14 Semaphorins: structure & functions Luca Tamagnone MD Laboratory of Cancer Cell Biology The elucidation of the functional role and molecular mechanisms by which Semaphorin genes control the invasiveness of tumor cells and the formation of metastases will prompt the development of innovative diagnostic and therapeutic approaches. Rationale Study of the molecular mechanisms that regulate tumor invasion and metastatic dissemination, with focus on the signals mediated by Semaphorins, acting in tumor cells and in cells of the tumor microenvironment. Results In preclinical murine models, semaphorin 3E/Plexin D1 signaling pathways drive the metastatic dissemination. Furthermore, the expression of Sema3E in primary human colorectal tumors correlates with the formation of distant metastases. This suggests that the expression of semaphorin 3E/Plexin D1 in human tumors represents an independent prognostic factor for patients stratification. Furthermore, in preclinical models in vivo, this signaling pathway driving tumor progression can be blocked by a modified variant of Sema3E (UNCL-Sema3E). This molecule shows strong anti-angiogenic and anti- metastatic activities. Finally, the receptor Neuropilin-1 controls the signaling pathway mediated by EGFR, a major oncogene driving tumor progression, targeted by innovative therapeutic approaches. Selected references Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J, Neufeld G,Tamagnone L. Neuropilin- 1-dependent regulation of EGFreceptor signaling. Cancer Res. 2012, 72: Tamagnone L. Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer. Cancer Cell. 2012, 22: Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, Mazzone M, Neufeld G,Tamagnone L. Tumour growth inhibition and antimetastatic activity of a mutated furinresistant Semaphorin 3E isoform EMBO Mol Med. 2012, 4: Projects and goals (i) To identify and to characterize novel semaphorin signaling pathways in control of tumor progression, by regulating tumor cell behavior and/or the stromal microenvironment; (ii) to understand the molecular mechanisms that mediate semaphorin functions in cancer, including the identification of new signal transducers associated with receptor complexes, (iii) to validate new molecular tools specifically targeting the signaling pathways Team Michael Rehman, Sabrina Rizzolio, Lorena Capparuccia, Chiara Battistini, Gabriella Cagnoni, Gurrapu Sreeharsha, Massimo Accardo Uncle-Sema3E is an engineered form of Semaphorin 3E, which concomitantly inhibits tumor angiogenesis and metastasis, by dismantling receptor complexes at the cell surface. 14 The mechanisms of cancer onset and progression

15 Dynamic control of cell adhesion in the normalization of tumor blood vessels The pharmacological modulation of integrin function can be therapeutically exploited to improve the biodistribution of anti-neoplastic drugs and counteract the hypoxiadriven metastatic dissemination of cancer cells. Guido Serini MD PhD Laboratory of Cell Adhesion Dynamics Selected references Valdembri D, Serini G. Regulation of adhesion site dynamics by integrin traffic. Curr. Opin. Cell Biol. 2012, 24: Sandri C, Caccavari F, Valdembri D, Camillo C, Veltel S, Santambrogio M, Lanzetti L, Bussolino F, Ivaska J, Serini G. The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. Cell Res. 2012, 22: Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo E. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J. Clin. Invest. 2009, 119: Rationale The binding of cells to the surrounding extracellular matrix is mediated by a class of adhesive receptors known as integrins, which can assume active or inactive conformations, respectively characterized by high or low affinity binding to the extracellular matrix. Results We showed how the modulation of integrin conformation and traffic is a key aspect of the molecular signals through which semaphorins control via their receptors plexins the correct morphogenesis of the vascular system; an abnormal control of these signals underpins the alterations that characterize tumor blood vessels. Finally, we found out how restoring the physiological inhibitory control of integrins by semaphorin can effectively prevent such vascular abnormalities, thus improving blood supply and penetration of anti -neoplastic as well as counteracting metastatic dissemination. Projects and goals Characterization of the mechanisms and molecular determinants responsible for: (i) inhibition of the adhesive function of endothelial cells by the secreted semaphorins; (ii) the selective control of active integrin traffic in endothelial cells. Molecular variants of semaphorin endowed with greater affinity for the receptor will be generated by mutagenesis and their potential therapeutic efficacy will be experimentally tested in transgenic models of cancer. Team Chiara Camillo, Noemi Gioelli, Chiara Sandri Semaphoring blood vessel cell adhesion The mechanisms of cancer onset and progression 15

16 New targets for the anti-angiogenic therapy Enrico Giraudo PhD Laboratory of Transgenic Mouse Models The better understanding of the anti-metastatic and normalizing effects of Sema3s on tumor blood vessels, will allow to design new strategy to overcome the resistance to the anti-angiogenic therapy. Rationale Some of the proteins that regulate the interaction between cell-matrix and cell-cell, such as Class 3 Semaphorins (Sema3s), are involved in the regulation of tumor angiogenesis and in the formation of metastasis, therefore, representing new targets for anti-angiogenic therapy Results Employing preclinical mouse models of cancer we described for the first time Sema3A as an endogenous angiogenesis and tumor inhibitor that is turn off during cancer progression. Sema3A re-expression by somatic gene transfer into different tumor types, significantly impaired angiogenesis, blocked tumor growth and metastasis formation, by normalizing the vasculature and inhibiting cancer hypoxia. Recently we demonstrated that the treatment of several mouse models of cancer with Sema3A, by inducing tumor blood vessel normalization and improving cancer tissue oxygenation, efficiently overcame the evasive resistance to the anti-angiogenic therapy induced by clinically approved drugs, such as Sunitinib and DC101, blocking metastasis and enhancing the survival. Moreover, Sema3A, improving vessel perfusion, significantly improved the delivery of chemotherapeutic drugs to the tumors and enhanced their efficacy. Selected references Serini G, et al. Class 3 semaphorins: physiological vascular normalizing agents for anti-cancer therapy. J. Intern. Med. 2013, 273: Maione F,et al. Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J. Clin.Invest. 2012, 122: Meda C,et al. Sema4A exerts a pro-angiogenic effect by enhancing VEGF-A expression in macrophages. J. Immunol. 2012, 188: Casazza A,et al. Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med. 2012, 4: Projects and goals (i) to employ Sema3A super-agonists mutants as new compounds to overcome the evasive resistance to the anti-angiogenic therapies, to halt metastasis formation and to normalize tumor vessels; (ii) to assess the efficacy of combining Sema3s or other axon guidance cues delivery with conventional anti-angiogenic drugs to block metastases dissemination using different mouse models of cancer; (iii) to identify the mechanisms by which Semas, their receptors and other axon guidance cues regulate stroma normalization, tumor invasiveness and metastases formation. Team Federica Maione, Stefania Capano, Donatella Regano 16 The mechanisms of cancer onset and progression

17 Role of membrane receptor endocytosis in the dissemination of metastatic cells. Knowing the mechanisms that control the downregulation of receptors involved in metastatic cell dissemination provides the rationale for the generation of innovative anti -neoplastic drugs. Letizia Lanzetti PhD Laboratory of Membrane Trafficking Selected references Palamidessi A, Frittoli E, Ducano N, Offenhauser N, Sigismund S, Kajiho H, Parazzoli D, Oldani A, Gobbi M, Serini G, Di Fiore PP, Scita G, Lanzetti L. The GTPase-activating protein RNtre controls focal adhesion turnover and cell migration. Curr Biol. 2013, 23: Lanzetti L. A novel function of Rab5 in mitosis. Small GTPases. 2012, 3: Serio G, Margaria V, Jensen S, Oldani A, Bartek J, Bussolino F, Lanzetti L. Small GTPase Rab5 participates in chromosome congression and regulates localization of the centromere-associated protein CENP-F to kinetochores. Proc Natl Acad Sci U S A. 2011, 108: Rationale Metastatic cancer cells, in order to spread, must activate a process known as invasive growth. The invasive growth program relies on the activation of plasma membrane receptors that are essential for proliferation and migration of metastatic cells in the surrounding tissues. Among these receptors, a key role is played by the family of adhesive receptors integrins and by the tyrosine kinase receptor Met. Several molecules finely regulate their activation and localization to the plasma membrane. Our unit studies some of these proteins, such as the small GTPase Rab5 and its effectors, whose function is to control the endocytosis of the receptors, their removal from the cell surface, and their downregulation. Results (i) We have isolated a novel regulator of growth factor-mediated cell migration. This molecule, named USP6NL, by turning off the GTPase Rab5, inhibits the endocytosis of adhesive receptors strongly reducing cell motility; ( ii ) we have also identified a novel function of Rab5 in the correct segregation of chromosomes during cell division. Projects and goals (i) To identify the molecular mechanisms that control the traffic of integrins and of the Met receptor in cancer cells characterized by increasing degrees of invasiveness; (ii) to study the effects caused by antibodies and catalytic inhibitors in the endocytosis and downregulation of tyrosine kinase receptors; (iii) to characterize the role of Rab5 and of its molecular network during the division of normal and cancer cells. Team Emanuela Pupo, Nadia Ducano Figure 1. Recruitment of the Rab5 GTPaseactivating protein RN-tre to adhesive sites. The mechanisms of cancer onset and progression 17

18 From neuronal biology to neoplastic progression Marco Arese PhD Laboratory of Neurovascular Biology The identification of molecular keys that mediate the relationship between tumor cells, blood vessels and nerves will contribute to the definition of a new class of therapeutic targets. Rationale We want to exploit the presence of proteins of nervous origin in the integrated tumor tissue, and all the relative knowledge deriving from the field of neurobiology, to bring new therapeutic tools in oncology. Neurexin and Neuroligin, two neuronal synaptic proteins, are the main objectives. Results Neurexin and Neuroligin are produced not only by neurons but also by cells of the vascular system, and they promote the formation of new blood vessels in experimental models of embryonic development and tumor angiogenesis. We generated a monoclonal antibody against an isoform of Neurexin that inhibits angiogenesis. Functionally, Neurexin and Neuroligin cooperate with VEGFA, the most studied pro-angiogenic factor, and with the adhesive receptor integrin alpha 6 beta 1, an important mediator of tumor angiogenesis. We also showed that Neurexin and Neuroligin are produced by tumor cells and that the expression of Neuroligin is strongly reduced during colorectal cancer ( CRC) progression. The reconstitution of its expression in CRC cells restricts the growth of the tumor. These data support the hypothesis that Neuroligin acts as a tumor suppressor in CRC. Selected references Rissone A, Foglia E, Sangiorgio L, Cermenati S, Nicoli S, Cimbro S, Beltrame M, Bussolino F, Cotelli F, Arese M. The synaptic proteins neurexin and neuroligin synergize with extracellular matrix-binding vascular endothelial growth factor a during zebrafish vascular development. Arterioscler Thromb Vasc Biol. 2012, 32: Bottos A, Rissone A, Bussolino F, Arese M. Neurexins and neuroligins: synapses look out of the nervous system. Cell Mol Life Sci. 2011, 68: Rissone A, Sangiorgio L, Monopoli M, Beltrame M, Zucchi I, Bussolino F, Arese M, Cotelli F. Characterization of the neuroligin gene family expression and evolution in zebrafish. Dev Dyn. 2010,239: Projects and goals We intend to : (i) define the cellular roles of Neurexin and Neuroligin in nerves, blood vessels and tumor cells; (ii) define the role of Neurexin and Neuroligin as mediators of communication between the tumor and its environment in two contexts : a) in the release of paracrine factors that modulate angiogenesis and neurogenesis b ) in the direct contacts between tumor cells and nerve cells (neuroneoplastic synapses) (iii) determine the molecular pathway by which Neurexin and Neuroligin play their roles in tumor or vascular cells, and the extent to which the neuronal machinery is recruited by these cells. Team Margherita Pergolizzi, Laura Bizzozero, Elena Riccitelli Tumor cells associated to a nervous axon in a perineural invasion model 18 The mechanisms of cancer onset and progression

19 Cellular and molecular mechanisms sustaining tumor angiogenesis All target therapies, including antiangiogenic therapies, are far from the wished results. However antiangiogenic regimens are an important tool for solid tumor treatment. Our studies aim at understanding the complexity of angiogenic process in physiology. Federico Bussolino MD Laboratory of Vascular Oncology Selected references Bussolino F, Giraudo E, Serini G. Class 3 semaphorin in angiogenesis and lymphangiogenesis. Chem Immunol Allergy. 2014, 99:71-88 Marchiò S, Astanina E, Bussolino F. Emerging lymphae for the fountain of life. EMBO J. 2013,32: Napione L et al. IL-12-dependent innate immunity arrests endothelial cells in G0-G1 phase by a p21(cip1/ Waf1)-mediated mechanism. Angiogenesis. 2012, 15: Marchiò S, et al. A complex of alpha6 integrin and E-cadherin drives liver metastasis of colorectal cancer cells through hepatic angiopoietin-like 6. EMBO Mol Med. 2012,4: Rationale Tumor angiogenesis is a validated target to fight solid tumor. However, clinical results are far from the expectations coming from animal models that clearly demonstrated that the inhibition of VEGF pathway halts tumor progression. In this context our main goal is to study the circuits between cancer and vascular cells to obtain new knowledge useful for envisaging the therapeutic approaches. Results (i) PLX4720, a specific inhibitor of the mutated kinase BRAFV600E, promotes vascular normalization and disease stabilization in preclinical models of colorectal cancers and melanomas; (ii) during embryo development VEGFR2 expression and activity is regulated by membrane proteins, including Neuropilin-1 and integrins and a specific co-regulatory mechanism occurring in embryonic stem cells drives the differentiation towards vascular or neural cell compartment; (iii) by combining bioinformatics and gene-silencing - based approaches we identified Tfeb, as a key transcription factor involved in epithelial-mesenchymal and in endothelial-mesenchymal transitions; (iv) VEGFR2 and Tie-2, which is the receptor for angiopoietins, form different complexes with integrins, which modulate the temporal and spatial signalling responses. Projects and goals (i) To study the circuits between stroma and cancer cells in 3D cultures (ii) to analyse tumour growth in mouse models carrying fibroblasts or endothelial cells genetically modified; (iii) to analyse by systems biological techniques of VEGF network, to identify new druggable targets ; (iv) to analyse the transcriptome of stroma and vascular cells isolated from cancer tissues, which do not respond to anti-angiogenic; (v) to identify of the methylome in models of resistance to anti-angiogenic therapies; (vi) to study the role of mixed regulatory circuits between transcription factors, micrornas and long-non coding RNAs in tumour. Team Elena Astanina, Valentina Comunanza, Gabriella Doronzo, Lucia Napione, Alessio Noghero, Davide Corà, Maria Alvaro, Anna Gualandris The mechanisms of cancer onset and progression 19

20 Cell migration in tumor angiogenesis and invasion Luca Primo PhD Laboratory of Cell Migration The identification of molecular mechanisms involved in tumor cell migration will allow to prevent the metastatic dissemination by pharmacologic inhibition. Rationale To develop strategies able to counteract the metastatic dissemination we want to define molecular mechanisms that may differentiate invasive cancer cells from their non-motile counterparts, and the relationship between tumour and non-tumour cells during cell migration. Cancer cells spread from the initial site of tumour growth acquiring an invasive phenotype characterized by both the loss of cell-cell interactions and increased cell motility. Vascular cells migrate into tumor mass forming new vessels in a process called tumor angiogenesis. Results We demonstrated that PDK1, the pivotal molecule in the PI3K signalling pathway, was necessary for endothelial and breast cancer cell migration. Now we are characterizing the pathway linking PI3K/PDK1 to the actin cytoskeleton, integrins and contraction, and how these pathways regulate motility in carcinoma and endothelial cells. We showed that integrin alpha6 is upregulated during tumor angiogenesis and it was involved in the endothelial sprouting process. We developed new three-dimensional culture systems that in combination with conventional cell biology approaches, allow studying collective and directional cell migration. Selected references Seano G, Chiaverina G, Gagliardi PA, di Blasio L, Sessa R, Bussolino F, Primo L. Modeling human tumor angiogenesis in a three-dimensional culture system. Blood. 2013, 121: Gagliardi PA, et al. Phosphoinositidedependent kinase 1 controls breast tumor growth in a kinase-dependent but Aktindependent manner. Neoplasia. 2012, 14: Primo L, et al.increased expression of alpha6 integrin in endothelial cells unveils a proangiogenic role for basement membrane. Cancer Res. 2010,70: Sessa R, et al.the mir-126 regulates angiopoietin-1 signaling and vessel maturation by targeting p85. Biochim Biophys Acta. 2012, 1823: Projects and goals The focus of our research is to understand why and how endothelial and cancer cells spread through the body. Specific aims: (i) to study the role of PI3K- PDK1 signalling in tumor angiogenesis and invasion; (ii) to characterize the molecular mechanisms activated by PI3K-PDK1 during cell migration; (iii) to develop and improve experimental 3D models of collective cell migration; (iv) to provide integrative mathematical and computational models simulating the morphogenetic and invasive processes of vascular and tumor; (v) to decipher the role of vascular basement membrane and pericytes in tumor angiogenesis and invasion; Team Laura Di Blasio, Alberto Puliafito, Giulia Chiaverina, Paolo Gagliardi Endothelial cells sprout from human umbilical arterial rings embedded in extracellular matrix gel, forming new capillary structures. 20 The mechanisms of cancer onset and progression

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