High Mobility Group Box 1 protein orchestrates tissue regeneration via CXCR4

10th December 2018.  
Marco Bianchi, San Raffaele University, Milan

On the 10th of December 2018 Marco Bianchi, of Università San Raffaele, will give a seminar entitled High Mobility Group Box 1 protein orchestrates tissue regeneration via CXCR4 at 5.00 pm in the College lecture theatre.  In his talk ME Bianchi will discuss the signaling role of HMGB1 (High Mobility Group Box 1) protein as Damage Associated Molecular Pattern (DMAP) protein. DAMPs are molecules that are normally present inside cells, and whose extracellular presence signals that some cell has died or risks doing so. HMGB1, as the prototypical DAMP, signals tissue damage and triggers inflammation. This is a major area of research in cancer biology, crucial for understanding the somatic evolution of cancer. 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.

Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated.High Mobility Group Box 1 (HMGB1) is a nuclear protein that, when released on injury, triggers inflammation. Remarkably, extracellular HMGB1 recruits inflammatory cells when it is fully reduced, and activates them when a disulfide bond forms between two cysteines. We have now found that fully reduced HMGB1 is also involved in tissue regeneration: it orchestrates muscle and liver regeneration via CXCR4 receptor, whereas disulfideHMGB1 and its receptors TLR4/MD-2 and RAGE (receptor for advanced glycation end products) are not involved. Injection of HMGB1 accelerates tissue repair by acting on resident muscle stem cells, hepatocytes, and infiltrating cells. The nonoxidizable HMGB1 mutant 3S, in which serines replace cysteines, promotes muscle and liver regeneration more efficiently than the wildtype protein and without exacerbating inflammation, by selectively interacting with CXCR4. Overall, our results show that the reduced form of HMGB1 coordinates tissue regeneration and suggest that 3S may be used to safely accelerate healing after injury in diverse clinical contexts.

ME Bianchi graduated in Biology at the Università di Milano in 1980, and soon after moved to Yale University, joining the Radding lab and studying molecular aspects of recombination catalyzed by RecA, a bacterial protein. On returning to the Università di Milano in 1983, he started looking for equivalent proteins in eukaryotes. This work blossomed when he moved in 1986 to the EMBL in Heidelberg, as an independent Staff Scientist: he isolated a protein that bound Holliday junctions, recombination intermediates formed by DNA molecules swapping helices. After joining the University of Pavia as an Associate Professor in 1989, he showed that this protein, HMGB1, was the founding member of so called “architectural proteins” that distort and bend DNA as chaperone to promote the assembly of multiprotein-DNA complexes. Since 1992 he is at San Raffaele, where he is currently a Professor of Molecular Biology, and where he identified HMGB1 as the first DAMP, a class of molecules that had been predicted by the dogma-changing “Danger Theory” of immunology.

[1] Tirone M, Tran NL, Ceriotti C, Gorzanelli A, Canepari M, Bottinelli R, Raucci A, Di Maggio S, Santiago C, Mellado M, Saclier M, François S, Careccia G, He M, De Marchis F, Conti V, Ben Larbi S, Cuvellier S, Casalgrandi M, Preti A, Chazaud B, Al-Abed Y, Messina G, Sitia G, Brunelli S, Bianchi ME* and Vénéreau E* (2018) High Mobility Group Box 1 orchestrates tissue regeneration via CXCR4. J Exp Med 215: 303-18.  doi: 10.1084/jem.20160217.
[2] Bianchi ME, Crippa MP, Manfredi AA, Mezzapelle R, Rovere Querini P and Venereau E (2017) High Mobility Group Box 1 protein orchestrates responses to tissue damage via inflammation, innate and adaptive immunity, and tissue repair. Immunol Rev 280: 74-82. doi: 10.11

Immunofluorescence of skeletal muscle, one of the targets of the HMGB1-CXCR4 signalling pathway.

MYC-dependent dynamics of transcriptional regulation

26th November 2018.  
Mattia Pelizzola, Italian Institute of Technology, Milan

On the 26th of November 2018 Mattia Pelizzola of the Italian Institute of Technology branch in Milan will give a seminar entitled MYC-dependent dynamics of transcriptional regulation at 2.00 pm in the College lecture theatre.  In his talk M Pelizzola will discuss extensive studies from his laboratory that have enabled in depth understanding of the complex gene dynamics and regulation enabled by the transcription factor Myc, the product of the MYC proto-oncogene and a master regulator of cell proliferation.  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.

Overexpression of the MYC transcription factor causes its widespread interaction with regulatory elements in the genome but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of RNA and RNAPII dynamics following MYC activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing, and mathematical modeling. Altogether, our results shed light on how overexpressed MYC alters the various phases of the RNAPII cycle, and leads to pervasive post-transcriptional regulation.

Mattia Pelizzola graduated in Biotechnology in 2001 at the Milano-Bicocca University. Following a PhD in computational biology, he spent 4 years in the States for two postdocs, first at the Yale University, and later on at the Salk Institute. In 2011 he moved back to Milan to start his own group at the Center for Genomic Science of the Italian Institute of Technology, located within the IFOM-IEO campus. His research currently focuses on the characterization of epigenomics and epitranscriptional determinants of RNA dynamics, and how these are altered in disease conditions. His group employes an interdisciplinary approach, which combines experimental and computational methods, including metabolic labelling of nascent RNA, epitranscriptome profiling and their integrative analysis through mathematical modelling.

[1] De Pretis et al. Genome Res 27:1658 (2017).

Fluorescence in situ hybridisation with a Myc gene probe demonstrates amplification of the Myc gene in cancer cells.

Metabolic modulation of haematopoietic stem cells

22th November 2018.  
Nicola Vannini, Ludwig Institute, Lausanne, Switzerland

On the 22nd of November 2018 Nicola Vannini of the Ludwig Institute for Cancer Research at Lausanne will give a seminar entitled Metabolic modulation of hematopoietic stem cells at 2.00 pm in the College lecture theatre.  In his talk N Vannini will discuss new data demonstrating how metabolic modulation of haematopoietic stem cells impact on their functions. This is a newly uncovered and potentially important level of regulation of stem cells behaviour.  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.

Cellular metabolism is recently emerging as a potential regulator of stem cell fate (Sahin and Depinho 2010, Suda, Takubo et al. 2011, Zhang, Khvorostov et al. 2011), constituting a crucial regulator of the HSC pool (Gan, Hu et al. 2010, Gurumurthy, Xie et al. 2010, Nakada, Saunders et al. 2010). The energy demand of quiescent HSCs relies on anaerobic glycolisis, which has to be rapidly switched to oxidative phosphorylation to enable hematopoietic differentiation (Takubo, Nagamatsu et al. 2013, Yu, Liu et al. 2013). Consistently, hematopoietic stem and progenitor cells belong to a 6-9% population of the entire bone marrow (BM), characterized by low mitochondrial activity,(Simsek, Kocabas et al. 2010) and their metabolic profiles have been associated with their localization in hypoxic regions of the BM(Parmar, Mauch et al. 2007, Simsek, Kocabas et al. 2010). Here we show that mitochondrial activity is a functional predictor of HSC engraftment both in vivo and in vitro and its modulation is capable to displace the LT-HSC/ST-HSC equilibrium in vivo by maintaining LT-HSC and increasing ST-HSC pools. Distinct hematopoietic compartments show specific increases in mitochondrial activity during commitment. Furthermore, mitochondrial activity resolves the function of stem and progenitor cells. In LKS cells (lin-cKit+Sca1+) efficient long term engraftment is retained in a subpopulation with low mitochondrial activity (TMRM low). Similarly, long and short term engraftment potential is restricted to TMRM low LKS-CD150+CD34- and LKS-CD150+CD34+ populations respectively. Considerably low mitochondrial activity discriminates HSCs retaining engraftment potential after in vitro culture. Modulation of mitochondrial metabolism in mice, supplemented with the metabolic modulator nicotinamide riboside (NR)(Canto, Houtkooper et al. 2012), increases the ST-HSC compartment which is critical in driving hematopoiesis during the short post-transplant period via mitophagy induction.  Accordingly, limiting BM transplant shows a dramatic improvement of survival in mice treated with NR compared to untreated ones, as predicted by faster platelet and neutrophil recoveries. Thus mitochondrial metabolism is a critical functional marker for LT-HSC, ST-HSC and in vitro cultured cells, and it reveals novel strategies to modulate the balance between hematopoietic compartments with possible significant clinical impact.

Nicola Vannini after his MSc degree in Biological Sciences obtained at the University of Parma, moved to La Jolla (CA) where he worked for two years at the Burnham Institute in the laboratory of Prof. John C. Reed and Prof. Giovanni Paternostro studying the metabolic basis of cardiac aging. Afterwards he moved back to Italy in order to complete his doctoral studies. In that period he worked at the National Institute for Cancer Research in Genova under the supervision of Dr. Adriana Albini and Prof. Douglas Noonan. His research topic was on the development of nutritional interventions as strategy to prevent tumor progression and angiogenesis, with particular focus on anti-inflammatory processes. After his studies Nicola Vannini has worked in the laboratory of stem cell bioengineering directed by Prof. Matthias Lütolf at the EPFL as postdoctoral fellow. There he developed a semi-automated system to analyze hematopoietic stem cell (HSC) fate at single cell level and, most recently, discovered important metabolic features regulating HSC function. In 2014 he continued his work in the laboratory of Prof. Olaia Naveiras and in collaboration with Prof. Johan Auwerx at the EPFL, where he developed targeted metabolic interventions capable to manipulate HSC fate. Since March 2016 Nicola Vannini is project leader at the Ludwig Center for Cancer Research (Lausanne branch) within the group of Prof. George Coukos. His primary research goals are the understanding of metabolic changes occurring during aging in the hematopoietic and immune compartments. Lastly he is currently developing targeted therapies that can prevent/revert the aging processes and consequently improve tumor immunotherapy and immunosurveillance. Specific interests include metabolic treatment for immunotherapy non-responders, metabolic reprogramming of myeloid biased HSC in aged and chemotherapy-treated patients, development of novel methods to boost blood reconstitution in transplanted patients and understanding the metabolic features of T cell exhaustion.

[1] Vannini N*, Campos V, Girotra M, Trachshel V, Rojas-Sutterlin S, Tratwal J, Ragusa S, Stefanidis E, Ryu D, Rainer PY, Nikitin G, Giger S, Semilietof A , Yersin Y, Cheng WC, Tauzin L, Pirinen E, Ratajczak J, Canto C, Sizzano F, Palini A, Petrova TV, Vanhecke D, Nahimana A, Duchosal MA, Ho PC, Deplanke B, Coukos G, Auwerx J, Lutolf MP and Naveiras O*. The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance. Cell Stem Cell, Under final revisions
[2] Roch A, Giger S, Girotra M, Campos V, Vannini N, Naveiras O, Gobaa S, Lutolf MP. Identification of functional artificial niches by single hematopoietic stem cell fate analyses. Nat Commun. 2017
[3] Vannini N, Girotra M, Naveiras O, Nikitin G, Campos V, Giger S, Roch A, Auwerx J, Lutolf MP. Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nat Commun. 2016
[4] Vannini N, Roch A, Naveiras O, Griffa A, Kobel S, Lutolf MP. Identification of in vitro HSC fate regulators by differential lipid raft clustering. Cell Cycle. 2012

Segmental duplication in human disease, diversity and evolution

19th November 2018.  
Giuliana Giannuzzi, University of Lausanne, Switzerland

On the 19th of November 2018 Giuliana Giannuzzi of the University of Lausanne will give a seminar entitled Segmental duplication in human disease, diversity and evolution at 2.00 pm in the College lecture theatre.  In her talk G Giannuzzi will discuss the mechanisms as well as the evolutionary implications of the duplications of segments of chromosomes.  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.


Segmental and gene duplications in the human genome are important for human genetic variation, disease and evolution. They represent human genome trade-offs between the possible adaptive function of duplicated genes mapping to these segments and their potential priming of pathogenic rearrangements. One example is the 16p11.2 locus, where recurrent copy number variation (CNV) is mediated by a complex set of segmental duplications. The deletion and duplication are associated with autism, schizophrenia, and reciprocal defects in head size and body weight. We interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs and found that transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in corresponding mouse models, suggesting that ciliary dysfunction contributes to 16p11.2 pathologies.We reconstructed the evolutionary history of the locus and discovered that it had been dramatically reorganized during hominid evolution. This series of genomic changes includes the Homo sapiens-specific duplication of the BOLA2 (BolA family member 2) gene, a gene involved in iron homeostasis, approximately 282 thousand years ago. This duplication that predisposes our species to the recurrent pathogenic 16p11.2 CNV, is absent from the genomes of our extinct relatives Neanderthal and Denisovan. It is apparently under selection (P<0.0097) and nearly fixed in the human lineage. Preliminary data on the possible functional role of BOLA2 duplication in 16p11.2 pathology and evolution of human-specific features will be presented. This region exemplifies that in the future we should comprehensively study structurally composite and repetitive regions of the human genome that predispose to pathogenic rearrangements while embedding human-specific genes, to unravel their role in disease, complex traits and evolution of human-specific features.

G Giannuzzi studied Medical Biotechnology and Molecular Medicine and obtained a PhD in Genetics and Molecular Evolution from the University of Bari. During her PhD she spent one year as visiting student in the laboratory of Prof. Evan Eichler, University of Washington, Seattle, where she worked on the evolution of the primate LRRC37 gene family. In 2012 she joined the laboratory of Prof. Alexandre Reymond of the University of Lausanne as a postdoc to study the molecular signatures associated with the evolution, diversity and disease of the 16p11.2 region of the human genome.


[1] Nuttle X*, Giannuzzi G*, Duyzend MH, Schraiber JG, Narvaiza I, Sudmant PH, Penn O, Chiatante G, Malig M, Huddleston J, Benner C, Camponeschi F, Ciofi-Baffoni S, Stessman HA, Marchetto MC, Denman L, Harshman L, Baker C, Raja A, Penewit K, Janke N, Tang WJ, Ventura M, Banci L, Antonacci F, Akey JM, Amemiya CT, Gage FH, Reymond A, Eichler EE. *equally contributing. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. Nature. 2016 Aug 11;536(7615):205-9.

[2] Migliavacca E, Golzio C, Männik K, Blumenthal I, Oh EC, Harewood L, Kosmicki JA, Loviglio MN, Giannuzzi G, Hippolyte L, Maillard AM, Alfaiz AA; 16p11.2 European Consortium, van Haelst MM, Andrieux J, Gusella JF, Daly MJ, Beckmann JS, Jacquemont S, Talkowski ME, Katsanis N, Reymond A. A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology. Am J Hum Genet. 2015 May 7;96(5):784-96.

A diagramatic representation of gene duplication in A thaliana,

Multi-omic analysis of epigenetics and RNA modifications

15th November 2018.  
Luca Pandolfini, University of Cambridge, UK

On the 15th of November 2018 Luca Pandolfini of the Gurdon's Institute at the UUniversity of Cambridge will give a seminar entitled Multi-omic analysis of epigenetics and RNA modifications at 2.00 pm in the College lecture theatre.  In his talk L Pandolfini will discuss how a multi-omic approach may offer a robust path to the discovery of important celllular regulatory mechanisms based on epigenetics or RNA modifications.This is a novel and powerful approach to the study of developmental and disease processes and 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.

To unravel the complexity of cell systems it is necessary to comprehensively consider as many descriptors of a cell state as possible (e.g. RNA expression, miRNA and protein levels, and mRNA loading on RISC complex or on translating ribosomes). This talk presents an overview of different projects distilled from a multi-omic approach, which allowed the identification of unexpected yet interesting molecular mechanisms. These include the maintenance of ground state pluripotency via mRNA translation control (1) and the role of METTL3 methyltransferase in sustaining AML leukaemia (2). I will provide a brief historical context to RNA modifications and I will also present unpublished data regarding how m7G methylation of miRNAs controls cancer cell migration.

L Pandolfini obtained his PhD from Scuola Normale Superiore di Pisa in 2015, under the supervision of Prof. Federico Cremisi, with a project aimed at dissecting the miRNA-mediated translation control of stem cell priming to differentiation (1). The same year he moved to the Gurdon Instute, Cambridge (UK) to work as a Research Associate in Tony kouzarides' lab. Has been studying the novel field of RNA modification epigenetics (or 'epitranscriptomics'). In particular, the focus of his post-doctoral research has been the development of new 'wet' and bioinformatic techniques for mapping RNA modifications, in order to study their role in cancer biology (2).

[1] Pandolfini et al., 2016 RISC-mediated control of selected chromatin regulators stabilizes ground state pluripotency of mouse embryonic stem cells - Genome Biol. 2016 May 6; doi: 10.1186/s13059-016-0952-x.
[2] Barbieri et al., 2017 Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control - Nature. 2017 Dec 7;552(7683):126-131. doi: 10.1038/nature24678.

A short RNA molecule forming an RNA duplex.  These short regulatory RNAs can alter the fate of RNA transcripts and hence gene expression.

A structural approach to mechanosensation

14th November 2018.  
Marco Lolicato, University of California San Francisco, USA

On the 14th of November 2018 Marco Lolicato of the University of California San Francisco will give a seminar entitled A structural approach to mechanosensation at 2.00 pm in the College lecture theatre.  In his talk M Lolicato will discuss his approach to the structural analysis of this important but poorly understood familty of mechanosensitive channels that enable the cells of living organisms to respond to their physical envirnoment. This is a novel an exiciting area of biological and medical research and 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.

Feeling the mechanical force is at the origin of the sensory perception. Mechanosensitive ion channels are the molecular machines able to ‘sense’ membrane tension via conformational changes adopted to follow bilayer deformations. We have investigated the polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channel of the TREK subfamily with a biophysical approach to unravel channel function. These channels generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K2P channels use a selectivity filter 'C-type' gate as the principal gating site. We have studied the molecular basis of selectivity and gating in the mechanosensitive members of the K2P family, TREK-1 and TRAAK, unravelling the mechanism of channel activation by gain-of-function mutants or small molecule binding. Our data suggest that the activation of these channels depends on concerted conformational changes both at the level of the selectivity filter and in the transmembrane region. However, understanding the structural basis of ion channel mechanosensation has been limited by the absence of a valid system to recreate membrane deformations in a structural biology setting. In order to study this mechanism I propose to combine the generation of conformation-selective artificial bilayers with single particle cryo-electron microscopy (cryo-EM) to image mechanosensitive ion channels. In fact, the lipid composition of an artificial bilayer can be modified to prompt conformational changes in ion channels, trapping the protein in ‘open’ or ‘closed’ states.

Marco Lolicato obtained his PhD from the University of Milano in 2012, under the supervision of Prof. Anna Moroni and Prof. Martino Bolognesi, with a project aimed at uncover the mechanism for the different behavior of three hyperpolarization- activated, cyclic nucleotide gated channels1. Later in 2013, he has been appointed as post-doc at the University of California San Francisco in the United States in the laboratory of Prof. Daniel Minor. During his post-doc he has studied the molecular basis of selectivity and gating in ion channels by X-ray crystallography2,3, Cryo-electron microscopy4 and functional studies. Since 2017 he is an Associate Specialist at UCSF and he continues to investigate the structure and function of mechanosensitive ion channels.

[1] Lolicato, M. et al. Tetramerization Dynamics of C-terminal Domain Underlies Isoform-specific cAMP Gating in Hyperpolarization-activated Cyclic Nucleotide-gated Channels. J. Biol. Chem. 286, 44811–44820 (2011).
[2] Lolicato, M., Riegelhaupt, P. M., Arrigoni, C., Clark, K. A. & Minor, D. L. Transmembrane Helix Straightening and Buckling Underlies Activation of Mechanosensitive and Thermosensitive K2P Channels. Neuron 84, 1198–1212 (2014).
[3] Lolicato, M. et al. K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site. Nature 593, 2587–368 (2017).
[4] Dang, S. et al. Cryo-EM structures of the TMEM16A calcium-activated chloride channel. Nature 552, 426–429 (2017).

Structure of the mechanosensitive channel Piezo1. Elife 6: -- (2017).

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.

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.

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 ( 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.

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

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.

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.

[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.

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.

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.


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.


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.

[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.

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.

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.

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.

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

Migrating cancer cells in culture.


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