In human cells, two meters of DNA sequence are compressed into a nucleus whose linear size is five orders of magnitude smaller. Deciphering how this amazing structural organization is achieved and how DNA functions can ensue in the environment of a cell’s nucleus represent central questions for contemporary biology.

Here, I embrace this challenge by establishing a comprehensive framework of microscopy and sequencing technologies coupled with advanced analytical approaches, aimed at addressing three fundamental highly-interconnected questions: 1) What are the design principles that govern DNA compaction? 2) How does genome structure vary between different cell types as well as among cells of the same type? 3) What is the link between genome structure and function? To this aim, we have devised a powerful method for Genomic loci Positioning by Sequencing (GPSeq), which allows genome-wide measurements of the distance of genomic loci to the nuclear periphery. Using GPSeq, we are generating reproducible maps of radial genome organization in human cells, in order to reveal radial gradients of genetic and epigenetic features as well as gene expression in various cell and tissue types. In parallel, we are developing high-end microscopy tools for simultaneous localization of dozens of genomic locations at high resolution in thousands of single cells.

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Dr. Marcus Conrad is director of the Institute of Metabolism and Cell Death at the Helmholtz Zentrum München in the field of metabolic cell death signalling and drug discovery. His research focus is concerned with the study of a recently recognized form of regulated necrotic cell death, now known as ferroptosis. Ferroptosis is a metabolic form of necrotic cell death characterized by the iron-dependent oxidative destruction of cellular membranes. Ferroptosis  is emerging as the underlying cause of a number of diseases such as neurodegeneration, tissue ischemia/reperfusion injury and cancer. By studying cells and mouse models for the key regulator of ferroptosis glutathione peroxidase 4 (GPX4), he has pioneered this field and has made a series of landmark discoveries that have greatly helped to understand the molecular mechanisms of this cell death paradigm. He has further identified the second, glutathione-independent ferroptosis regulator, called ferroptosis suppressor protein-1 (FSP1), which can fully complement loss or inactivation of GPX4. Moreover, he has reported the first in vivo applicable ferroptosis inhibitor, liproxstatin-1, whose improved derivatives are currently undergoing preclinical development. Dr. Conrad has published more than 100 scientific articles, which have received more than 9000 citations. Furthermore, he holds three patents and has been twice awarded the prestigious m4 Award for translating basic knowledge into innovative drugs for novel therapies.

Five most important publications

Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M (2008) Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8:237-248.

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Eukaryotic genomes are replete with sequences derived from selfish genetic elements, such as transposable elements and endogenous viruses. In this talk, I will present a snapshot of the myriad ways these elements have influenced the biology of their hosts. I will summarize a body of evidence illustrating how both coding and non-coding sequences prefabricated and dispersed by mobile elements have been repurposed repeatedly during vertebrate evolution to foster biological novelties –-and particularly in transcriptional regulation.

This is joint work with Matthias Meller and Kaspar Rufibach (Roche, Basel). Progression-free (PFS) and overall survival (OS) are arguably the two most important time-to-event outcomes in oncology. Decades ago, multistate methodology has been developed to jointly model PFS and OS, but practical efforts have often fallen back on a more traditional random variables approach. The latter typically assumes that PFS equals OS with probability zero only, or that there is progression after death, or even that a patient has more than one survival time. This is in contrast to the multistate approach which simply assumes that a patient currently in the state of being free of progression may either die without prior progression diagnosis or move thru states "progression diagnosis" and "death after progression". A practical motivation is that novel therapies may get market approval based on PFS benefit, but reimbursement may depend on OS benefit, and the statistical question is that of the dependence between PFS and OS. Time permitting, we will offer a tirade against latent times and modeling events after death (with a nod to simulations) as well as remarks on how to bootstrap time-to-event data. For the latter, wild or weird bootstrapping may be the method of choice if data are dependent as they are in event driven randomized clinical trials.

References:

Meller M, Beyersmann J, Rufibach K: Joint modeling of progression-free and overall survival and computation of correlation Measures. Statistics in Medicine 2019, 38, pages 4270-4289

Bluhmki T, Schmoor C, Finke J, Schumacher M, Socié G, Beyersmann J: Relapse- and immunosuppression-free survival after hematopoietic stem-cell

transplantation: How can we assess treatment success for complex time-to-event endpoints? Biology of Blood and Marrow Transplantation 2020 (Early View)

Cancer is a highly complex system that evolves asexually under high mutation rates and strong selective pressures. Cancer genomics efforts have identified genes and regulatory elements driving cancer development and neoplastic progression. The detection of both significantly mutated (positive selection) and undermutated (negative selection) genes is completely confounded by the genomic heterogeneity of the cancer mutation rate. Here, I present an approach we recently developed in order to address mutation rate heterogeneity to increase the power and accuracy of selection inference. Using a hierarchical model, we infer the distribution of mutation rates across genes that underlies the observed distribution of the synonymous mutation count within a given cancer type. This enables the inference of the probability of nonsynonymous mutations under neutrality without additional parameters, however explicitly taking into account cancer-type-specific mutational signatures, which are known to be highly distinct. In addition to detecting an excess in the total number of muta- tions, we then augmented our test through integrating information at the single-nucleotide level, exposing a ”selection mutational signature”. Based on a model that accounts for the extended sequence context (> 5-mers) around mutated sites, this second component of the test identifies genes with an excess of mutations in unusual nucleotide contexts, which deviate from the characteristic context around neutrally evolving passenger mutations. I will show that the inclusion of this context test increases power to detect cancer driver genes particularly when the fraction of selected nucleotides on a gene is small. Using the combined test, we discovered a catalogue of well-known cancer driver genes as well as a long tail of novel candidate cancer genes with mutation frequencies as low as 1% and functional supporting evidence.

The identification of these breakthrough innovations at the earliest stage is the grail of most stakeholders at the interface of research and development. The goal of this workshop is to share practice from France and aboard ensuring that the next big thing would be properly identified, protected, maturated and transferred from academia to the industry ensuring a successful development that would reach researchers and patients at some point.

Researchers, clinicians and industries have witnessed the emergence of broad range of innovations over the past years in Oncology, including but not limited to cell and gene therapies, machine learning and immunotherapy.

Being able to forecast the next one is a tricky game of changing targets, as drug candidates or methods might be already under development within labs. Therefore, this conference aims to:

Raise the awareness of all the stakeholders involved in the improvements of cancer diagnosis and therapies.

Have experts from multiple domains including both scientific and business perspective sharing their experience and their opinions on the future of oncology.

Promote discussion on the future of therapies and networking among the participants.

This event is organised by Institut Curie with the support of FINDMED and PSL and Labiotech.eu

13h30 Introduction

The place of Tech transfer in France and abroad - hosted by Isabelle Peltier-Bressac, Founder & CEO at AttLeva Conseils

Tech transfer option: entrepreneurship or license ? hosted by Bruno Rostand, Innovation & Entrepreneurship Director - PSL

Coffee Break

From discovery to early stage clinical trial hosted by Amaury Martin, Head of tech transfer office - Institut Curie

From innovation to gold standard hosted by Timothé Cynober, Business Manager - Institut Curie

Conclusion - Amaury Martin presenting Live illustration drawn during the conference by Emmanuelle Kiener (Manuka)

Cocktail & Networking

For more information, contact the organizer: timothe.cynober@curie.fr

Séminaire proposé par Timothe Cynober,
Business Manager - Institut Curie

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Assistant Professor, Department of Genetics

University of Georgia

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Marsupials diverged from eutherian mammals ~190 million years ago and thus occupy a "sweet spot" in the evolution of mammals from their reptilian ancestors. Consequently, they have provided many fascinating insights into the evolution of viviparity, placentation and early development. My career has similarly evolved – from a deep interest in early cell lineage differentiation and embryonic patterning to numerous questions pertaining to the evolution of reproduction and development (Evo-Devo-Repro). More recently, I have even endeavoured to make myself useful by applying novel genetic tools to the conservation of marsupials and eradication of invasive vertebrate pests in Australia.

152 publications; Citations: Google Scholar 56250 | Web of Science 37350, h-index 82, i10-index 139

All publications in Pubmed:

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Search&db=pubmed&term=Meissner%20Alex%20OR%20Meissner%20Alexander

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The research focus of the lab is to understand the relevance of mitochondrial dynamics in health and disease.  The morphology of mitochondria is inextricably linked to its many essential functions in the cell and we are interested in understanding the relationship between mitochondrial shape changes and metabolism in the context of acquired and inborn human diseases.  I will discuss ongoing work using genetic screens to identify factors novel regulators and modulators of mitochondrial morphology in cells from patients with mitochondrial genetic diseases and the lessons we are learning regarding the importance of balanced mitochondrial dynamics.  I will also discuss the relevance of mitochondrial fission in cardiac metabolism and the connections between mitochondria, cell death, inflammation and heart failure in novel models developed by our lab.

Accurate DNA replication is essential for genomic stability and cancer prevention. Homologous recombination is important for high-fidelity DNA damage tolerance during replication. How the homologous recombination machinery is recruited to replication intermediates is unknown. We recently showed that a Rad51 paralog-containing complex, the budding yeast Shu complex, recognizes and enables tolerance of abasic sites during DNA replication predominantly on the lagging strand.  We performed whole genome sequencing in Shu complex mutants upon MMS exposure and uncovered a mutation signature consistent with accumulation of abasic sites and an additional lesion, 3-methylcytosines.  In bacteria and mammalian cells, the ALKB family of enzymes recognizes and repairs 3-methylcytosines.  However, budding yeast do not have an ALKB homolog.  Therefore, it remains unknown how 3-methycytosines are removed and repaired.  Here, we provide evidence that the yeast Shu complex has evolved to recognize and promote error-free bypass of 3-methylcytosines during DNA replication.  Preliminary data suggests that Shu complex function in error-free bypass of abasic sites and 3-methylcytosines is likely conserved in higher eukaryotes.

Drug resistance dissemination by horizontal gene transfer remains poorly understood at the cellular scale. Using live-cell microscopy, we reveal the dynamics of resistance acquisition by transfer of the F conjugative plasmid encoding the tetracycline-efflux pump TetA. We show that the entry of the ssDNA plasmid into the recipient cell is rapidly followed by complementary strand synthesis and expression of newly acquired genes. TetA production is enhanced by zygotic induction resulting in the optimized establishment of resistance. In the presence of protein synthesis-inhibiting antibiotics, acquisition of resistance becomes strictly dependent on AcrAB-TolC multidrug efflux pump. We demonstrate that AcrAB-TolC is required for maintenance of protein synthesis activity and therefore TetA production following plasmid acquisition. This work uncovers a novel essential role of multidrug efflux systems in the acquisition of drug-specific resistance by horizontal gene transfer and helps to understand the dissemination of antibiotic resistance in bacteria.