Contenuti

Mutational signatures in lung and liver tumours

8th November 2018.  
Laura Riva, Sanger Centre, Hinxton, UK

On the 8th of November 2018 Laura Riva of the Sanger Centre at Hinxton,  will give a seminar entitled Mutational signatures in environmental, carcinogen-induced lung and liver tumours at 2.00 pm in the College lecture theatre.  In her talk L Riva will discuss the genomic alterations that accompany the development and progression of experimental and human tumours as a foundation for understanding the basis for cancer progression, an area of research with a major impact on future therapies including, notably, precision or personalised approaches to cure. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
By analysing the catalogue of the somatic mutations present in several cancer genomes, it is possible to understand the mutational processes active in different tumours. In this seminar, I will describe the mutational signatures identified in cancer genomes and their association with many processes that drive cancer. In addition, I will introduce some computational methods that have been developed to discover mutational signatures in cancer genomes. Furthermore, I will describe the signatures of mutational processes present in the genome of mouse tumours following exposure to several carcinogens.

Biography
L Riva received a PhD in Bioengineering at the Politecnico di Milano in 2007. In 2006, she moved to Massachusetts Institute of Technology (MIT), joining the Fraenkel lab as a visiting student supported by the Progetto Rocca MIT-PoliMi Program. There, she developed ResponseNet, a systems biology approach to reveal mechanistic connections between genetic and transcriptional data by integrating multi-omics data. During her postdoctoral training at MIT (2007-2010), supported by the Merck-MIT Postdoctoral Fellowship, she contributed to the understanding of deregulated transcriptional networks through the use of NGS technologies. After receiving the AIRC/Marie Curie International Fellowship in Cancer Research, she joined the Pelicci lab at the European Institute of Oncology in Milan, where she started her research in cancer genomics. In 2012, she joined the Centre for Genomic Science (CGS@SEMM) at the Instituto Italiano di Tecnologia in Milan (https://www.iit.it/centers/cgs-semm) as a team leader, and with her team she developed computational methods to analyse and interpret human cancer genomics data, focusing  to the identification of driver genes. In 2017, she joined the Wellcome Trust Sanger Institute in Cambridge (UK), as a Principal Bioinformatician in the Experimental Cancer Genetics lab (Adams lab). She is currently studying mutational signatures of cancer development in response to environmental carcinogens.


Reference
Alexandrov LB et al. Signatures of mutational processes in human cancer. Nature. 2013 Aug 22;500(7463):415-21. doi: 10.1038/nature12477.

 
Image
Graphical representation of a gene expression network. Courtesy of QG Fu, Tongji University, Shanghai.

Single-cell transcriptomics in leukaemia stem cells

5th November 2018.  
Alice Giustacchini, University College London, UK

On the 5th of November 2018 Alice Giustacchini, of University College London will give a seminar entitled Single-cell transcriptomics uncovers distinct molecular signatures and dysregulated pathways in stem cells in chronic myeloid leukaemia at 2.00 pm in the College lecture theatre.  In her talk A Giustacchini will discuss the technological and scientific advances enable by single cell analysis of leukaemia cells and how these data may help reconstructing the somatic evolution of individual cancers.  Tumour progession is a crucial area of research in cancer biology with a major impact on future therapies including, notably, precision or personalised approaches to cure. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
Molecularly targeted therapies can frequently induce remission in cancer, but can rarely achieve complete disease eradication, with resulting risk of disease relapse and progression. Chronic myeloid leukemia (CML) is a good example of this, with rare, propagating stem cells (SCs) that are incompletely eradicated by BCR-ABL-directed tyrosine kinase inhibitors (TKIs). Multiple lines of evidence support that CML-SCs are selectively resistant to TKI therapy, leading to disease relapse following treatment discontinuation. A better characterization of the biological pathways sustaining therapy resistance in CML-SCs is crucial for the development of new therapeutic strategies to achieve disease eradication. However, it has proven challenging to characterize this clinically relevant population of CML-SCs, as they reside in the same immunophenotypic compartment as the normal hematopoietic stem cells (HSCs), from which they cannot be reliably distinguished. To this aim, we developed a novel method that allows for simultane­ous single-cell RNA sequencing and high-sensitivity, targeted muta­tion detection. The unprecedented resolution on CML-SCs that our analysis achieved allowed for the characterization of distinct molecular signatures of CML-SCs from diagnosis through remission and disease progression, with potential implication for future refinement of targeted therapies in CML.

Reference
[1] Giustacchini A, Thongjuea S, Barkas N, Woll PS, Povinelli BJ, Booth CAG, Sopp P, Norfo R, Rodriguez-Meira A, Ashley N, Jamieson L, Vyas P, Anderson K, Segerstolpe Å, Qian H, Olsson-Strömberg U, Mustjoki S, Sandberg R, Jacobsen SEW, Mead AJ. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nature Medicine. 2017.  2017 Jun;23(6):692-702.

[2] Nucera S*, Giustacchini A*, Boccalatte F, Calabria A, Fanciullo C, Plati T, Ranghetti A, Garcia-Manteiga J, Cittaro D, Benedicenti F, Lechman ER, Dick JE, Ponzoni M, Ciceri F, Montini E, Gentner B, Naldini L. *first co-author. miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia. Cancer Cell. 2016 June 13;29(6):905-21.

Biography
Alice Giustacchini obtained her PhD from San Raffaele University in 2013, under the supervision of Prof. Luigi Naldini, with a project focusing on the role of microRNAs in the regulation of hematopoietic stem cell functions. Later in 2013, she moved to the UK to undertake a post-doctoral project in the laboratory of Prof. Sten Eirik Jacobsen at the University of Oxford. During her post-doc she focused on the development of novel single-cell approaches to resolve cell heterogeneity in leukemic stem cells during therapy response. Since 2017 she joined University College London where she is leading her own group focusing on the characterization of metabolic heterogeneity in myeloid leukemia stem cells and its implication for therapy response.

 
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Leukaemic cells under the microscope.

Unravelling Cell Division Mechanisms to Understand Cancer

30th October 2018.  
Pier Paolo D'Avino, University of Cambridge, UK

On the 30th of October 2018 Pier Paolo D'Avino, of the University of Cambridge will give a seminar entitled Unravelling cell division mechanisms to understand cancer at 2.00 pm in the College lecture theatre.  In his talk PP D'Avino will discuss the complex regulation of the cell cycle of animal cells and will highlight the different stages in which cancer cells can subvert cell cycle check points causing uncontrolled cell division and multiplication. This is a major area of research in cancer biology, the importance of which has been recognised earlier this centrury with Nobel Pizes to P Nurse an T Hunt and confirmed by the development of new anti-cancer compounds aimed at restoring cell cycle control in cancer cells. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract

Cell division is one of the most fundamental biological processes. It is essential for growth, development and reproduction in many organisms, including humans. Cell division faithfully partitions the genomic information between the two daughter cells and errors in this process have been implicated in many human diseases, such as chromosomal syndromes, sterility and cancer. In many cancers, defects in cell division generate chromosomal instability (CIN), which consists of recurrent chromosomal changes that contribute to tumorigenesis by altering the balance of critical growth and death pathways. Although its role in cancer onset is still debated, CIN has been implicated in cancer evolution, diversification and heterogeneity, is associated with poor clinical outcome and drug resistance, and has been suggested to play a role in the development of metastases. Thus, a thorough understanding of the mechanisms controlling cell division may lead to understand the origins of CIN and its role in cancer development and to the development of novel therapeutic treatments for cancer pathologies.  PP D'Avino's research interests focus on the study of the mechanisms and signalling pathways that govern cell division in eukaryotic cells and their de-regulation in cancer cells, with particular emphasis on how the activity of mitotic proteins and protein complexes are regulated by phosphorylation. In this talk, I will present our recent efforts to dissect the complex regulatory cross-talks between mitotic kinases and phosphatases during cytokinesis and to understand the origins and consequences of CIN in the development of oesophageal adenocarcinoma.

Biography

Pier Paolo D'Avino was born in Naples where I also obtained my laurea in Biology in May 1990 and my PhD in Molecular and Cellular Genetics in 1995 - both at the University Federico II. My PhD focused on the mechanisms of hormonal regulation of gene expression using Drosophila melanogaster as model system. In August 1995 he moved to Salt Lake City, Utah, USA to study how hormones regulate cell shape changes and tissue remodelling during metamorphosis in Drosophila, in the laboratory of Prof Carl Thummel, Howard Hughes Medical Institute and Department of Human Genetics of the University of Utah.He obtained an EMBO long term fellowship to move to Cambridge, UK, in January 1999 to join the group of Prof Michael Ashburner at the Department of Genetics of the University of Cambridge as an independent researcher.  In January 2001, I started working on the mechanics and regulation of cytokinesis in the group of Prof David Glover, always at the Department of Genetics. In 2004, after obtaining a BBSRC research grant, I was appointed Senior Research Associate and Director of Research, always at the Department of Genetics. In January 2009, he was appointed Lecturer in Cell Biology at the Department of Pathology of the University of Cambridge, where I currently teach Molecular and Cellular Biology of Cancer to Natural Sciences, Medical and Veterinary students and investigate the mechanisms and signalling pathways that govern cell division in eukaryotic cells and their de-regulation in cancer cells. Pier Paolo D'Avino is happily married and have two wonderful teenage daughters. He enjoy cooking, hiking, and running. In his - little - free time he enjoys reading books and watching movies/documentaries on science, science fiction, crime and ancient roman history. Finally, he follow sports: F1 motor racing, rugby and football. Has been a Ferrari “tifoso” since the age of 14 and, as all Neapolitans, was born to support the Napoli football team.


Reference
[1] McKenzie, C. and D’Avino P.P. (2016) Investigating cytokinesis failure as a strategy in cancer therapy. Oncotarget, 7(52):87323-87341 (doi: 10.18632/oncotarget.13556)
[2] D’Avino P.P. and Capalbo L. (2016) Regulation of midbody formation and function by mitotic kinases. Seminars in Cell and Developmental Biology, 53:57-63.
[3] D’Avino P.P. (2017). Citron kinase - renaissance of a neglected mitotic kinase. Journal of Cell Science, 130(10): 1701-1708; doi: 10.1242/jcs.200253.

 
Image
A fibrosarcoma cell undergoing cell division. Courtesy of M Kyle Hadden, University of Connecticut

 

Metabolic Pathways as Regulators of Epithelial Mesenchymal Transition

25th October 2018.  
Paolo Ceppi, Friedrich-Alexander University, Erlangen-Nuremberg

On the 25th of October 2018 Paolo Ceppi, of the Friedrich-Alexander University at Erlangen-Nuremberg, will give a seminar on Metabolic pathways as regulators of epithelial-to-mesenchymal transition at 2.00 pm in the College lecture theatre.  In his talk P Ceppi will connect the metabolic features, outlined iniitially by O Warburg nearly one century ago, with key biological processes of cancer cells, for example the ability of epithelial cancer cells to acquire a migratory phenotype (so-called epithelial mesenchymal transition). This is a novel and important area of research in cancer biology. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
The most lethal features of cancer are chemoresistance and metastatic dissemination. In many cases, both are attributed to the presence of cells driven by de-differentiation processes like the epithelial-to-mesenchymal transition (EMT) and the cancer stem cell (CSC) program, which can foster a clinical relapse. Recently, our lab and others showed that some metabolic pathways can exert a powerful regulatory role on cancer cell de-differentiation and promote cancer aggressiveness by driving EMT/CSC. Identifying the whole network of metabolic pathways controlling the de-differentiation processes could be highly impactful in the field of drug repositioning because, in contrast to currently known EMT effectors and mediators, several inhibitors for metabolism enzymes are already in clinical use for the treatment of not tumor-related diseases. Metabolism-based therapeutic strategies could contribute to reduce the devastating effects of aggressive cancers.

Biography
Paolo Ceppi received his PhD from the University of Torino and was then a postdoc in the Peter lab at the Northwestern University in Chicago. Since 2015 he is a Junior Group Leader at the Interdisciplinary Center of Clinical Research (IZKF) of the FAU University of Erlangen-Nuremberg, in Germany. His team focuses on the mechanisms that regulate cancer plasticity and at studying the epithelial-to-mesenchymal transition, the cancer stem cells and the association between cancer de-differentiation and sensitivity to chemotherapy. He received funding and awards from the US Department of Defense, the International Association for the Study of Lung Cancer, the German Cancer Aid and the German Research Foundation.

Reference
Schwab et al. Cancer Research 78:1604, 2018
Siddiqui et al. J Pathol 242:221, 2017
Ceppi et al. Nature Communications 4:5238, 2014
Ceppi et al. Oncogene 33:269, 2014

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Migrating cancer cells in culture.

 

From Big Data to Mechanisms. How Context Dependent Phenotypes Vary Across Cells

22nd October 2018.  
Peter Blattmann, ETH, Zürich

On the 22nd of October 2018 Peter Blattmann, of the Eidgenössische Technische Hochschule (ETH) at Zürich, will give a seminar on From big data to mechanisms. Understanding how context dependent phenotypes vary across cells at 2.00 pm in the College lecture theatre.  In his talk P Blattmann will give key examples of the reach of mass-spectrometry based systems biology approaches in order to study protein networks and cellular functions. This is an emerging field of research that will have huge impact for our understanding of biological processes and disease. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
In individuals, heterogeneous drug response phenotypes result from a complex interplay of dose, drug specificity, genetic background, and environmental factors, thus challenging our understanding of the underlying processes. Here we present an approach to explain drug response differences in a panel of cell lines combining mass spectrometry-based quantification of molecular phenotypes with subsequent integration of the quantitative data using logic modeling. The approach was applied to cellular cholesterol regulation, a biological process with high clinical relevance. The phenotypes elicited by various targeted pharmacologic or genetic treatments were profiled by quantifying >3000 proteins and >1000 metabolites using mass spectrometry. Based on this data and a prior knowledge network, we generated cell-line-specific models that quantified the processes beneath the idiotypic intracellular drug responses and could identify which processes in the model varied between the cell lines. The models revealed that in addition to drug uptake and metabolism further cellular processes showed significant pharmacodynamic response variability between cell lines, resulting in cell-line-specific drug response phenotypes. This study demonstrates the importance of integrating different types of quantitative systems-level molecular measurements with modeling to understand the effect of pharmacological perturbations on complex biological processes.

Biography
P Blattmann studied biochemistry at ETH Zurich and after his studies, he performed an internship at Genentech in South San Francisco. In 2008, he received a PhD-Fellowship from the European Molecular Biology Laboratory (EMBL) to perform his PhD studies in the Molecular Medicine Partnership Unit (MMPU), a department between EMBL and the University Hospital Heidelberg. In the groups of Dr. Rainer Pepperkok and Dr. Heiko Runz, he functionally characterized the genes reported by genome-wide association studies (GWAS) for blood lipid traits and cardiovascular disease using RNA interference, functional cellular assays, and high-content microscopy. In May 2013, he joined the Aebersold lab with the interest to better understand how complex biological processes vary between cell lines. Using proteomics (SWATH-MS/DIA) and cholesterol regulation as a model system, he has conducted a systems pharmacology study identifying how a large number of cellular factors determine the variable drug response across cell lines.

Reference
[1] P. Blattmann*#, D. Henriques, M. Zimmermann., F. Frommelt., U. Sauer, J. Saez-Rodriguez, and R. Aebersold* “Systems pharmacology analysis of cellular cholesterol regulation reveals large pharmacodynamic variability”, Cell Systems, 5, 604-619 (2017). https://doi.org/10.1016/j.cels.2017.11.002[2] P. Blattmann and R. Aebersold, “The advent of mass spectrometry-based proteomics in systems biology research” Encyclopedia of Cell Biology (ed. R. Bradshaw and P. Stahl), 1st Edition, Academic Press (2016). ISBN: 9780123944474. https://doi.org/10.1016/B978-0-12-394447-4.40030-1

Image
A typical protein network. Courtesy of AF Villaverde (University of Oxford, UK and Vigo Spain)

 

Cancer Stemness and Adaptive Immune Evasion in Hepatocellular Carcinoma

19th October 2018.  
Manlio Vinciguerra, Institute for Translational Medicine, Brno, Czech Republic

On the 19th of October 2018 Manlio Vinciguerra, of the Institute of Translational Medicine at Brno, will give a seminar on Cancer stemness and adaptive immune evasion in hepatocellular carcinoma at 2.00 pm in the College lecture theatre.  In his talk M Vinciguerra will discuss advances on the study of the origin of liver cancer cells and their ability to evade the immune system. These may have implications for our understanding of cancer biology and the development of future therapies liver cancer, a major cause of human death especially in Asian populations. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
Among the epigenetic mechanisms of control of gene expression, histone variants confer to the nuclear chromatin unique properties. Histone variants, mostly of canonical histones H2A, H2B and H3, have important roles in lineage commitment of stem cells, in somatic cell reprogramming to pluripotency and, in some cases, in the modulation of animal aging and life span.  MacroH2A1 is the largest histone variant in nature, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis (1,2). In hepatocellular carcinoma (HCC), the most common cause of death in people with liver cirrhosis, loss of the histone variant macroH2A1 induces cancer stem cells (CSCs) appearance and chemoresistance (3). CSCs exhibit stem cell like features and are responsible for tumor relapse and metastasis. How these CSCs interact with neighboring non-stem HCC cells and are cleared by the adaptive immune system is unclear. I will show that CSCs reprogram neighboring HCC cells into CSC-like cells that can evade the adaptive immune response. This effect is achieved through combined epigenetic and paracrine mechanisms, via loss of histone variant macroH2A1 and chemokine/cytokine depletion in the tumor microenvironment (4).

Biography
Dr. Manlio Vinciguerra, PhD, (born in Catania on 05.05.1976), currently holds a Principal Investigator position at the International Clinical Research Center (FNUSA-ICRC), in Brno, Czech Republic. He directs a research team of 20 scientists, focusing on (1) epigenetics, aging and liver cancer, and on (2) prevention of cardio-metabolic disorders. He has 17 years of research training and experience conducted in 6 different European countries (Italy, Netherlands, Switzerland, Germany, UK, Czech Republic).  His research has been funded by Telethon, Swiss National Fund for Research (SNSF), EMBO, AIRC, H2020, the European Regional Fund for Development (ERFD), government and pharmaceutical companies. He authored ~140 publications with cumulative IF=800, between research papers, reviews, editorials and book chapters. His H index is 34 and number of citations he received is >4300.

Reference
(1) Histone MacroH2A1: A Chromatin Point of Intersection between Fasting, Senescence and Cellular Regeneration. Lo Re O, Vinciguerra M. Genes (Basel). 2017 Dec 5;8(12). pii: E367. doi: 10.3390/genes8120367.
(2) DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression. Borghesan M, Fusilli C, Rappa F, Panebianco C, Rizzo G, Oben JA, Mazzoccoli G, Faulkes C, Pata I, Agodi A, Rezaee F, Minogue S, Warren A, Peterson A, Sedivy JM, Douet J, Buschbeck M, Cappello F, Mazza T, Pazienza V, Vinciguerra M. Cancer Res. 2016 Feb 1;76(3):594-606.
(3) Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma. Lo Re O, Fusilli C, Rappa F, Van Haele M, Douet J, Pindjakova J, Rocha SW, Pata I, Valčíková B, Uldrijan S, Yeung RS, Peixoto CA, Roskams T, Buschbeck M, Mazza T, Vinciguerra M. Hepatology. 2017 Sep 15. doi: 10.1002/hep.29519. [Epub ahead of print]
(4) manuscript in revision.

Image
A histological section of normal human liver

 

Stem Cell Models of Differentiation and Regeneration

18th October 2018.  
Virginie Sottile, University of Nottingham, United Kingdom

On the 18th of October 2018 Virginie Sottile, of the University of Nottingham (UK), will give a seminar on Stem cell models of differentiation and regeneration at 2.00 pm in the College lecture theatre.  In his talk V Sottile will discuss how stem cells biology has dramatically changed our understanding of cell dynamics and turnover in different tissues/organs and how these advances may impact on the therapy of degenerative diseases of the central nervous system and internal organs. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
Progenitors residing in adult organs represent a growing research focus for fundamental as well as translational approaches to regenerative medicine. While the ability to identify stem cells and manipulate their phenotype in vitro is opening new options for interventions to restore tissue cells and function, it is also posing new challenges in terms of translational control, lineage identification and targeted delivery. I will present some of the approaches my group is developing to address these aspects, using tissue-derived stem cells to model, induce and exploit differentiation towards therapeutically relevant lineages, with two prime systems: neural stem cells for CNS applications, and mesenchymal progenitors to target metabolic and skeletal conditions.

Biography
V Sottile studied Cell & Molecular Biology at the University of Nice (France), and carried out research in laboratories in Basel and Edinburgh on regulatory aspects of somatic and embryonic stem cell differentiation before joining Nottingham in 2001. She heads the Adult Stem Cell Biology group in the School of Medicine, where her lab focuses on the isolation, in vitro characterisation and differentiation of stem cells for regenerative medicine applications. Her research interests include neural stem cell biology, and Virginie’s group identified a new population of progenitors residing in the adult cerebellum[1], whose potential for neural tissue repair is currently under evaluation. The other core research interest in her group, the mesenchymal stromal/stem cell model present in bone marrow and other connective tissues, is exploited to identify new therapeutic approaches both as a molecular screening tool in vitro[2, 3] and as a cellular target for skeletal tissue regeneration strategies in vivo[4].

References
[1] Alcock et al. (2009) Cell Research
[2] Velickovic et al. (2018) Sci Rep.
[3] Surrati et al. (2016) Analyst
[4] France et al. (2014) J Tissue Eng Regen Med

Image
Courtesy of Sarita P Panula, Karolinska Institutet, Stockholm

 

PI3-Kinase in Metabolic Homeostasis and Tumour Progression

11th October 2018.  
Giovanni Solinas, University of Gothenburg, Sweden

On the 11th of October 2018 Giovanni Solinas, of the Institute of Medicine of the University of Gothenburg Sweden, will give a seminar on PI3-Kinase in Metabolic Homeostasis and Tumour Progression at 2.00 pm in the College lecture theatre.  In his talk G Solinas will discuss the multiple and pivotal role of PI3-kinase in cell behaviour and a major role in cancer progression. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) play a central role in signal transduction from different receptors, including growth factor receptors and the insulin receptor. PI3K signaling is frequently activated in most cancer types, as it is driven by most frequent driver genetic alterations in cancer. However, targeting PI3K signaling in cancer has been problematic, and most pan-PI3K inhibitors showed limited therapeutic index in cancer therapy. It was proposed that this is due to the role of PI3K signaling in the metabolic action of insulin. Indeed, PI3K inhibition causes insulin resistance leading to hyperglycemia and compensatory hyperinsulinemia that reactivates PI3K signaling in insulin-sensitive cancer cells. Our work aims at defining the role of specific PI3K isoforms in insulin signaling and tumor promotion, with the aim of developing novel therapies for cancer and obesity by targeting selected PI3K isoforms. 

Biography
Giovanni Solinas is a Professor of Molecular Medicine at the Institute of Medicine of the University of Gothenburg Sweden, and a principal investigator at the Wallenberg Laboratory for Cardiovascular and Metabolic Research. His research focuses on the study of the signaling pathways implicated in the pathogenesis of obesity-related diseases and in particular type-2 diabetes and cancer. Most notable contributions are the identifications of specific inflammatory signaling pathways linking obesity and metabolic dysfunctions, and his studies on the role of PI3Kγ signaling in obesity, metabolic inflammation, and glucose homeostasis. Dr Solinas is a peer reviewer for several international funding bodies and scientific journals, he is a member of the editorial board of Molecular Metabolism, and he served as member of the executive committee of the Swiss society for the Study of Obesity and Metabolism.

Reference
The role of PI3Kγ in metabolism and macrophage activation. G Solinas and B Becattini. Oncotarget 2017 (8) 106145-106146

Image
Crystal structure of PI3-kinase in complex with inhibitor. PDB accession: 4j6i.

 

Targeting Diseased Epigenomes by Tuning Mitochondrial Metabolism

8th October 2018.  
Carlo Gaetano, Istituti Clinici Scientici Maugeri, Pavia

On the 8th of October 2018 Carlo Gaetano, of the Istituti Clinici Scientifici Maugeri, will give a seminar on Targeting diseased epigenomes by tuning mitochondrial metabolism at 5.00 pm in the College lecture theatre. Epigenetics, namely the range of enzymatic and non-enzymatic DNA modifications that finely tune gene expression during development and tissue regeneration also play an important role in disease.  In his talk C Gaetano will address and discuss this latter area of research. All College students are invited to attend, especially those reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
The first part of the presentation will describe  the recently published outcome of an integrated metabolomics, transcriptomic and genomicapproach carried out in order to better understand the origin of epigenetic alteration evident in human  primary cardiac stromal cells obtained from diabetic patients undergoing cardiac surgery. This research, conducted in  collaboration  with  other  Institutions in  Europe, USA, and Australia, led to the characterisation of new small molecules targeting specific mitochondrial metabolic/epigenetic pathways controlling enzymes involved in DNA  methylation. The second part of my talk will present unpublished data about a new role for P300/CBP associated factor (PCAF) in regulating mitochondria acetylation and function during skeletal muscle differentiation.

Biography
C Gaetano heads a newly established Laboratory of Epigenetics at Istituti Clinici Scientifici Maugeri in Pavia (Italy). During his training he was Fogarty Fellow and Associate at the National Cancer Institute in the Molecular Genetics Section of the Pediatric Branch from 1989 until 1992, Bethesda (USA). He was a Visiting Scientist of the National Cancer Institute form may 1995 to September 1996 and then Visiting Associate Professor at McMaster University, Hamilton (CA) in 1999. From 1997 to 2012 he was Senior Scientist and Group Leader at the Laboratorio di Patologia Vascolare of the "Istituto Dermopatico dell'Immacolata-IRCCS". From May 2012 until December 2017 he was Professor of stem cell epigenetics and Director of the Division of Cardiovascular Epigenetics at the Department of Cardiology, Faculty of Medicine, Goethe University, Frankfurt-am-Main (DE). His major scientific interest throughout the years has been epigenetics applied to clinically relevant diseases. In recent years, hid laboratory established in vitro and in vivo human disease models with special attention to human primary cells isolated from volunteer donors including human cardiac stromal cells from non-diabetic and diabetic patients. The studies focused on the epigenetic consequences of environmental challenges (e.g. high glucose, UV radiation, chemicals) causing mitochondrial metabolic alterations and their effect on DNA conformation, integrity and function. Together with other Institutions in Europe and US, he is also characterising new small molecules targeting DNA methylation including DNA methyltransferases (DNMTs) and Ten-eleven-translocation (TET) enzymes.

Reference
Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by alpha-Ketoglutarate and TET-TDG Functional Reactivation. Spallotta, F. et al. Stable. Circulation Research 122, 31-46, 2018.

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Courtesy of the Royal Society of Chemistry.

 

Challenging Therapies for Muscular Dystrophies

4th October 2018.  
Giulio Cossu, University of Manchester

On the 4th of October 2018 Giulio Cossu, of the University of Manchestterl, will give a seminar on Challenging therapies for muscular dysttrophies at 5.00 pm in the College lecture theatre. Muscular dysttrophies constitute an important group of diseases that have posed exceptional challenges to scientists and physicians. G Cossu will review progress and will highlight the major remaining challenges that have to be overcome in order to ensure successful therapy. All College students are invited to attend, especially thse reading Medicine, Biology, Biotechnology and Pharmaceutical Sciences. The poster of the lecture can be downloaded here.

Abstract
In the last few years there has been significant advance in pre-clinical and clinical work of gene and cell therapy for muscular dystrophy. Currently there are several trials ongoing and more are expected to start. It is thus a time of expectation, even though many hurdles remain and it is unclear now whether they will be solved by current strategies or further improvements will be necessary. After reviewing current work in the field I will describe our current effort for an implemented protocol of cell therapy for muscular dystrophy. My laboratory has been working for many years on skeletal myogenesis and on the development of cell therapy protocols with stem cells for muscular dystrophy. We showed that neural tube (Vivarelli and Cossu, Dev. Biol. 1986) and dorsal ectoderm (Cossu et al., Development 1996) activate, through different Wnts, distinct myogenic programs in epaxial and hypaxial somitic progenitors. We also described myogenic cell heterogeneity (Cossu and Molinaro, Curr. Topics Dev. Biol. 1987) whose molecular basis has been recently elucidated (Messina et al. Cell 2010). We developed the first pre-clinical model for analysis of human myogenic progenitors in vivo (Salvatori et al., Hum Gene Ther. 1993), and discovered the myogenic potential of a bone-marrow derived, circulating progenitor cell (Ferrari et al., Science 1998). Our studies on unorthodox derivation of myogenic cells by non-somitic tissues (Tajbakhsh et al., Neuron 1994; Salvatori et al., J. Cell Sci. 1995) set the basis for the understanding of recruitment to myogenesis of non-myogenic cells, and the origin of multipotent mesoderm stem cells. We identified a mesoderm progenitor in the dorsal aorta (De Angelis et al. J Cell Biol. 1999), i.e. the mesoangioblast, able to contribute to mesoderm tissues upon transplantation (Minasi et al. Development 2002). Mesoangioblasts were used for the first successful cell therapy protocols of muscular dystrophy in mice and dogs (Sampaolesi et al. Science 2003; Nature, 2006). We characterized human mesoangioblasts as a subset of muscle pericytes (Dellavalle et al. Nature Cell Biol. 2007). Together, this data set the basis for a first clinical trial in Duchenne patients with stem cells (Cossu et al. EMBO Mol Med. 2015). We are currently optimising the protocol aiming at reaching clinical efficacy.

Biography
I am currently the Constance Thornley Professor of Regenerative Medicine at the University of Manchester. I received my MD degree from the University of Rome, then moved as Fogarty fellow at the University of Pennsylvania and in 1983 as Research Associate in Rome. In 1990 I spent an extended sabbatical at the Pasteur Institute in Paris. In 1992 I became Professor of Histology and Embryology in Rome. In 2000 I moved to Milan as Director of the Division of Regenerative Medicine at San Raffaele; in 2012 I moved as Professor of Human Stem Cell Biology to University College London and in 2013 to the University of Manchester. I began working as CAT member at EMA (2012-13). I am a member of EMBO, of the European Academy of Science, a fellow of the Academy of Medical Sciences and of Accademia dei Lincei. I am recognized for my work on muscle development and on cell therapy for muscular dystrophies. I have published more than 250 peer-reviewed papers and secured grants for more than15 M£

Image
Section of skeletal muscle under the light microscope.

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