Le Groupe Sein de l'Institut Curie - Hôpital à Saint-Cloud a, comme chaque année, le plaisir de vous inviter à sa demi-journée conscrée aux cancers de la femme, dans le but de présenter et de discuter ensemble les aspects pratiques de la prise en charge et l'évolution des connaissances dans ce domaine.

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Research Bio Overview:

Jamie Hackett is a group leader at the European Molecular Biology Laboratory (EMBL), within the Epigenetics and Neurobiology unit in Rome, Italy. He obtained his PhD at the University of Edinburgh, and completed postdoctoral training at the University of Cambridge, UK, under Prof. Azim Surani. The Hackett group investigates the fundamental principles of epigenetic regulation, from molecular mechanisms to organismal responses. They integrate environmental perturbations and precision (epi)genome editing technologies to dissect the mechanisms by which normal or aberrant chromatin states functionally participate in genome control and developmental programming. They also model the impact of induced epigenomic changes on intergenerational health and disease susceptibility. Key questions include:  

Selected Publications (link):

Policarpi C… Hackett JA (2024). Systematic epigenetic editing captures the context-dependent instructive function of chromatin modifications. Nature Genetics (in press).

Denboba … Hackett JA (2024). Paternal microbiome perturbations impact offspring fitness. Nature (in press).

Carlini V, Policarpi C & Hackett JA (2022). Epigenetic inheritance is gated by naïve pluripotency and Dppa2.  

EMBO Journal.

Gretarsson K & Hackett JA (2020). Dppa2 and Dppa4 counteract de novo methylation to establish a permissive epigenome for development. Nature Structural & Molecular Biology.

Tang WW… Hackett JA Chinnery PF, Surani MA. (2015). A unique gene regulatory network resets the human germline epigenome for development. Cell.

Hackett, JA… Surani A. (2013). Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science.

Oligodendroglia (OLG) mediate myelination of neurons, a process that allows efficient electrical impulse transmission in the central nervous system.  An autoimmune response in multiple sclerosis (MS) leads to OLG cell death, loss of myelin and neuropathology. Using single cell transcriptomics, we have previously identified disease-specific OLG populations in the EAE mouse model of MS and in human MS brain archival tissue, characterized by the expression of immune genes. 

By assessing chromatin accessibility and the transcriptome simultaneously at the single cell level at different stages of the disease course, we found that immune genes exhibit a primed chromatin state in mouse and human OLG in a non-disease context, compatible with rapid transitions to immune-competent states in MS. Moreover, we found dynamic and distinct transcriptomic and epigenomic responses of OLG subpopulations to the evolving environment in EAE mouse model of MS, which might modulate their response to regenerative therapeutic interventions in MS.

While single-cell genomics are powerful for investigating disease-specific cellular states, these methods involve isolating the tissue under study from its niche, leading to a loss of spatial information. Such information is essential for determining cell-to-cell communication in disease niches. We have applied in situ sequencing to investigate disease evolution in MS at a spatial level, both in the EAE mouse model of MS and in human post-mortem MS samples. We annotated disease neighborhoods during lesion evolution and found centrifugal propagation of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course.

We have also applied dBIT-Seq, a ligation-based method for deterministic barcoding in tissue, to probe different histone modifications and chromatin accessibility in the mouse brain tissue sections, either in an unimodal or simultaneously with transcriptomics. This spatial epigenome–transcriptome co-profiling has allowed us to identify cellular lineage progression and epigenomic priming events that precede transcription during development with spatial resolution. We are currently applying these methods to disease paradigms in MS, to uncover how transitions to pathological cellular states occur at epigenomic and transcriptomic levels.

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Long version (3,5 weeks, w/ practicals at Sorbonne University & Seminars at Institut Curie) : July 20th
Short Version (10 days, Seminars at Institut Curie) : September 1st

Institut Curie and Sorbonne Université organize their 15th International Developmental Biology course.

The aim of the program is to provide the participants a comprehensive coverage of the paradigms, problems and technologies of modern Developmental Biology paying particular attention to stem cells.

Training in theoretical and experimental aspects of normal and abnormal development is developed through a variety of embryonic systems using state-of-the-art instrumentation and methodology.

The program is proposed in two versions (more information available soon) so there will be two registration deadlines:

"Eterochromatin, a specialized type of chromatin, is crucial for gene regulation and genome stability. While we understand some of the structural and enzymatic components involved in heterochromatin formation, a complete picture of the underlying pathways remains elusive. To address this, we developed a systematic approach to identify factors involved in heterochromatin silencing in Schizosaccharomyces pombe. Using quantitative measures, iterative screens, and domain-specific heterochromatin reporters, we identified hundreds of mutants with altered silencing patterns. Surprisingly, most of these factors exhibited distinct qualitative and quantitative profiles, suggesting domain-specific functions. One such factor, the uncharacterized protein Dhm2, was found to be crucial for maintaining both constitutive and facultative heterochromatin. Interestingly, the loss of Dhm2 led to phenotypes similar to those seen in DNA replication-deficient mutants, indicating a potential link between DNA replication and epigenetic inheritance. Our findings highlight the intricate relationship between DNA replication and heterochromatin maintenance, providing new insights into the mechanisms underlying epigenetic inheritance".

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Organoids form through poorly understood morphogenetic processes in which initially homogeneous ensembles of stem cells spontaneously self-organize in suspension or within permissive three-dimensional extracellular matrices. Yet, the absence of virtually any predefined patterning influences such as morphogen gradients or mechanical cues results in an extensive heterogeneity. Moreover, the current mismatch in shape, size and lifespan between native organs and their in vitro counterparts hinders their even wider applicability. In this talk I will discuss some of our ongoing efforts in developing next-generation organoids that are assembled by guiding cell-intrinsic self-patterning through engineered stem cell microenvironments. I will also present recent examples of how we are using these engineered organoids for disease modeling, in particular in the area of solid tumors.

The loss of dopaminergic neurons during Parkinson’s disease (PD) is responsible for the hallmark motor impairment associated with the disease. The molecular mechanisms driving the disease process are still poorly understood. While the contribution of inflammation in PD is well established, a growing body of evidence supports a role for the long-lasting adaptive immune system in the disease. We showed that, in inflammatory conditions, the PD-proteins PINK1 and Parkin negatively regulate the presentation of mitochondrial antigens on MHC I molecules, a process referred to as MitAP (Mitochondrial Antigen Presentation). In the absence of PINK1, over-activation of this pathway engages autoimmune mechanisms leading to the activation of cytotoxic CD8+ T cells that may contribute to dopaminergic neurons (DNs) cell death. Using pharmacological and genetic approaches, together with OMICs analyses, we characterized here the MitAP pathway at the molecular cell level. Our data indicate that engagement of TLR4 during inflammation sequentially activates the stimulator of interferon genes (STING) and the unfolded protein response (UPR) to regulate both the innate inflammatory response and antigen presentation. Remarkably, the role of STING and the UPR in the presentation of self-antigens is regulated by LRRK2, a protein with GTPase and kinase activities linked with PD. These data highlight the fact that immune processes could be targeted for the development of therapeutic approaches to prevent or delay the onset of PD

Parental histone recycling and transfer are essential for restoring histone-carried epigenetic information. During DNA replication, parental nucleosomes bearing epigenetic marks are disrupted ahead of each replication fork to allow duplex DNA unwinding and subsequent DNA synthesis. To maintain the fidelity of the epigenetic landscape, parental histones are recycled and transferred to the newly synthesized strands. Accumulating evidence suggests the involvement of two critical groups of factors in parental histone transfer at replication forks. The first group consists of histone chaperones, which play a role in nucleosome assembly and disassembly coupled with replication. The second group comprises several replisome components that can bind histones and act as co-chaperones. In this presentation, I will discuss our recent progress in understanding the role of the histone chaperone FACT (facilitates chromatin transactions) in coordinating with replisome components to manage the recycling and distribution of parental histones at replication forks. We have discovered that FACT anchors to the replisome and facilitates the transfer of parental histones to both the leading and lagging strands. Specifically, I will detail how FACT collaborates with the Fork Protection Complex (FPC), composed of Tof1, Csm3, and Mrc1, to regulate parental histone recycling and distribution between the two daughter strands. First, we have identified a parental histone intermediate at the replication fork, which includes a fully evicted histone hexamer [(H3-H4)2-H2A-H2B], chaperoned by Spt16, Mcm2, and Tof1. Our findings show that Tof1, working with the histone-binding domain of Mcm2, facilitates the relocation of the FACT-escorted parental histone hexamer to the replisome front, enabling its transfer to the newly synthesized lagging strand DNA. Second, we have discovered that Mrc1 possesses a histone H3-H4 binding domain and plays a critical role in mediating the distribution of parental histones to the newly synthesized strands. Collectively, these findings support the idea that FACT collaborates with multiple replisome components to form a ternary complex of FACT-histones-replisome components essential for parental histone recycling and transfer. We propose that the efficient collaboration between histone chaperones and the replisome is crucial for maintaining the efficiency, balance, and symmetry of histone traffic during chromatin replication, ultimately supporting the inheritance of epigenetic information.

DNA double-strand break repair is an essential process ensuring the maintenance of genome integrity and recently, a transcription-coupled arm of DSB repair has been identified (named TC-DSBR for Transcription-Coupled DSB Repair). Using a cell line, called DIvA (for DSB Inducible via AsiSI), where multiples breaks are induced at annotated positions, combined with genome-wide, high throughput sequencing-based techniques (ChIP-seq, HiC...) we investigate the contribution of chromatin and chromosome conformation in the response to TC-DSB, induced in transcriptionally active loci. I will present our recent work, on the contribution of chromatin and Topologically Associating Domains (TADs) during DSB repair. More specifically we recently demonstrated the role of cohesin-mediated loop extrusion in establishing gammaH2AX on an entire TAD in cis to DSBs. We further provided evidence that when established, TAD stamped with gammaH2AX  further self-segregate in the nucleus, forming a novel DSB-induced chromatin compartment (the “D” compartment) that contributes to the activation of the DNA damage response. Finally, we recently identified the PER complex, a molecular device ensuring circadian oscillations, as a key component of TC-DSB Repair through a previously unsuspected role in positioning DSBs at the periphery of the nucleus.

Understanding protein expression across tissues and organisms is crucial for elucidating functional similarities and differences in physiological processes, which is essential for selecting the appropriate model organism in biomedical studies. We present a comprehensive analysis of protein repertoires across 25 tissues in Xenopus frogs, using advanced quantitative mass spectrometry to measure the levels of over 15,000 proteins. By comparing these profiles, we reveal tissue-specific expression patterns and identify conserved proteins shared across diverse organs. We explore evolutionary strategies of ubiquitous and tissue-specific proteins and discuss the search for 'missing' proteins that have vanished in human samples but appear in frogs.

Understanding the dynamic pathogenesis and treatment response in pulmonary diseases requires probing the lung at cellular resolution in real-time. Despite recent progress in intravital imaging, optical imaging of the lung during active respiration and circulation has remained challenging. Here, I introduce the crystal ribcage: a transparent ribcage that (i) allows truly multiscale optical imaging of the lung in health and disease from whole-organ to single cell, (ii) enables the modulation of lung biophysics and immunity through intravascular, intrapulmonary, intraparenchymal, and optogenetic interventions, and (iii) preserves the 3-D architecture, air-liquid interface, cellular diversity, and respiratory-circulatory functions of the lung. Utilizing these unprecedented capabilities on murine models of primary and metastatic lung tumors, respiratory infection, pulmonary fibrosis, emphysema, and acute lung injury we probed how disease progression remodels the respiratory-circulatory functions at the single alveolus and capillary levels. In cancer, we identified the earliest stage of tumorigenesis that compromises alveolar and capillary functions, a key state with consequences on tumor progression and treatment response. In pneumonia, we mapped mutual links between the recruited immune cells and the alveolar-capillary functions. We found that neutrophil migration is strongly and reversibly responsive to vascular pressure with implications for understanding of how lung physiology, altered by disease and anatomical location, affects immune cell activities. The crystal ribcage and its broad applications presented here will facilitate further studies of real-time remodeling of the alveoli and capillaries during pathogenesis of nearly any pulmonary disease, leading to the identification of new targets for treatment strategies.

Bio:

Hadi T. Nia is an Assistant Professor of Biomedical Engineering at Boston University. He received his B.Sc. from Sharif University of Technology and did his doctoral training at Massachusetts Institute of Technology (MIT) under the supervision of Drs. Alan Grodzinsky and Christine Ortiz. He then moved to Massachusetts General Hospital, Harvard Medical School for his post-doctoral training under the mentorship of Dr. Rakesh Jain where he studied the tumor microenvironment with a focus on the physical hallmarks of cancer. Hadi’s current research include developing novel models and tools for imaging the lung in real-time and at the cellular resolution to probe the links between the lung physics, biology, and immunity in health and disease. Hadi has received multiple awards for his research including NIH Director’s New Innovator (DP2), Sloan Research Fellowship, NSF CAREER, Beckman Young Investigator, DoD Idea Award, and NIBIB Trailblazer awards.

Course organizers:

Ana-Maria Lennon-Duménil (Insititut Curie, FR)

Eliane Piaggio (Institut Curie, FR)

María Soledad Matus (USS-Fundación Ciencia & Vida, CL)

Mario Rosemblatt (USS-Fundación Ciencia & Vida, CL)

Álvaro Lladser (USS-Fundación Ciencia & Vida, CL)

Mariana Maccioni (National University of Córdoba, CIBICI-CCT-CONICET, AR)

Nathalie Amzallag (Institut Curie, FR)

Inês Pires Pinheiro (Institut Curie, FR)

The Immunity and Cancer Unit of Institut Curie (INSERM U932) is organizing the 7th edition of the Advanced Course on Immunity and Cancer Immunotherapy.

In the context of ongoing cooperation projects with research teams in Chile and Argentina that have resulted in the prior organization of workshops in cell biology and immunology, this year’s edition is jointly organized with the Fundación Ciencia & Vida (Chile) and will be dedicated to multiple aspects of fundamental immunology and possible applications in cancer immunotherapy. The course will offer 4 days of lectures and discussions centered on the latest developments in innate immunity, myeloid and lymphoid cell biology, tissue immunity and the role of the microenvironment in immune activation, cancer immunity, as well as state-of-the-art cell therapy and cancer immunotherapy. Besides attending the lectures, the participants will have the opportunity to present their projects during two poster sessions, discuss with the speakers, attend workshops on open science and scientific integrity, and participate in a round table on career opportunities.

Expanding the links with Latin American research institutions, the Advanced course on Immunity and Cancer Immunotherapy is jointly organized with the 3rd Franco-Austral Course on Bioinformatics Applied to Immunology, taking place in Buenos Aires, Argentina, from October 30th to November 2nd, just before the 2024 meeting of the Latin American and Caribbean Association for Immunology.

The Advanced Course on Immunity and Cancer Immunotherapy is exclusively destined to Master students, PhD students and postdoctoral researchers from Latin American universities and/or research institutions.

The course is organized and funded by the LabEx DCBIOL, Institut Curie’s Advanced Training Office, Institut Curie’s Medico-Scientific Program in Immunotherapy, the Inserm CIC-1428, PSL University, Universidad San Sebastián, Centro BASAL Ciencia & Vida (ANID-FB210008) and Fundación Ciencia & Vida. The cell therapy session is organized and funded by the RHU EpCART, a structuring project funded by the French National Research Agency (ANR) in the framework of the France 2030 program.

The integration of mathematical models into clinical oncology has emerged as a powerful tool for understanding and predicting cancer dynamics, with applications ranging from forecasting tumor growth and identifying prognostic biomarkers to optimizing therapeutic response. This talk will provide an overview of recent advances in mathematical oncology, focusing on the role of quantitative models in unraveling the complexities of cancer progression and treatment.

At the Mathematical Oncology Laboratory (MOLAB), through close collaboration with biomedical institutions, we have built models that delve into key areas of cancer dynamics, including the discovery of universal scaling laws that govern tumor growth and metabolic demands across various tumor types, based on large patient cohorts. Another contribution has been the development of evolutionary models to capture tumor heterogeneity, offering novel biomarkers that predict patient outcomes by identifying regions of heightened proliferative activity at the tumor periphery. Through these interdisciplinary efforts, we aim to show how mathematical models are not only advancing our understanding of cancer biology but also driving innovations in personalized medicine and enhancing clinical decision-making. This talk will explore these developments and their transformative potential in cancer treatment.

It is now accepted that blood-derived immune cells and microbial products shape brain development, function, aging, and disease, yet the presence of such factors in the brain territory is limited. So how can they exert their powerful effect on the nervous system from afar?

The choroid plexus (CP) epithelium is a monolayer barrier tissue, which on the side facing the blood can sense such peripheral factors, and on the side facing the brain, produces the cerebrospinal fluid (CSF)–a liquid carrying nutrients and signaling molecules, which contacts nearly all brain cells, and ensures brain homeostasis. We study how the peripheral immune and microbial factors may shape brain function indirectly, via regulation of the CSF properties at the CP epithelium in brain development, normal physiological function, aging, and disease. Our goal is to identify fundamental principles of physiological brain regulation by the peripheral factors to pave the way for future investigation of the gut-blood-CP-brain communication circuit in neurological disease.

Research in the Parent lab aims at understanding the mechanisms by which cells reach sites of infection and injury. In particular, our work focuses on neutrophils, the most abundant leukocyte in human blood and first line of defense against insult. We found that, in response to primary chemoattractants, neutrophils secrete the secondary chemoattractant leukotriene B4 (LTB4), which dramatically amplifies the recruitment range of neutrophils to sites of infection or injury. LTB4 is synthesized from the cytosolic phospholipase 2 alpha (cPLA2α)-mediated release of arachidonic acid through the action of the cytosolic enzyme 5-lipoxygenase (5-LO), the endoplasmic reticulum/nuclear envelope-resident protein 5-lipoxygenase activating protein (FLAP) and leukotriene A4 hydrolase. Neutrophil activation triggers the packaging of the LTB4 synthesizing machinery within nuclear envelope-derived multivesicular bodies, which release exosomes that secrete LTB4 to recruit distant neutrophils to infected/injured sites. We also found that chemotaxing neutrophils release nuclear DNA in a non-lytic, rapid, and repetitive manner. The packaging of DNA occurs in the lumen of these same nuclear envelope-derived multivesicular bodies. The mechanisms underlying this response as well as its physiological consequence will be presented.

The widely anticipated revolution in biology, driven by the superpowers of GAI, has been slow to materialize. In this talk, we will discuss the concept, the obstacles, and examine two specific projects involving language and image analysis. The first case study involves extracting information from a specific type of biological literature—lifespan extension under pharmacological perturbation—where we aim to agglomerate experimental parameters over extensive body of published literature and automatically review and assess the quality of emerging studies in that context. The second project focuses on image analysis using a novel imaging technique, Stimulated Raman Microscopy, to characterize protein and lipid remodeling in various organs and tissues, to detect changes in a nested hierarchy of repetitive elements of tissue architectures and elucidate changes reflecting sex specificity, aging, and disease. We will anticipate what will be needed for a productive man-machine symbiosis to emerge in systems biology.

Ever since the 1953 determination of the structure of DNA, there have been repeated
discoveries that have been labelled the “secret of life.”  In this talk, I continue with that tradition by
asserting that however we define life, it is certain that the state of matter we call living
depends upon the expenditure of  energy.   I will explore a two-pronged approach.
First, we will tap into the power of order of magnitude thinking to explain the energy
budgets of cells, examining the relative costs of the processes of the central dogma,
motility, the maintenance of transmembrane gradients, macromolecular degradation
and beyond.  To really understand these processes, secondly, I will argue we need to measure
this kind of molecular accounting in space and time and to that end, will discuss
our recent efforts to measure the consumption of ATP in active matter collectives
of microtubules and their attendant kinesin motors.  Our measurements yield
power in units of ATPs per cubic micron per second and make it possible to
better understand the relation between energy expenditure and the emergence of
biological order such as is seen in the fascinating and enigmatic spindles of
dividing cells.

Le cours est dédié aux connaissances les plus actuelles articulant la biologie du développement et l'étude cellulaire et moléculaire des cancers. Les crêtes neurales et les mélanomes, depuis leur formation jusqu'à leur migration (métastases), ainsi que les médulloblastomes sont pris comme exemples. Le cours bénéficie d'une approche multidisciplinaire à multiples échelles (embryologie sur des modèles variés, biologie cellulaire, transcriptomique, imagerie...). Il se termine par des présentations des approches thérapeutiques.

Le cours est ponctué par des tables rondes sur les carrières dans le milieu académique ou dans l'industrie, sur la publication d'articles scientifiques ainsi que sur l'éthique en expérimentation animale. D'anciens étudiants du M2 GCD de Paris-Saclay viendront présenter leur parcours. Des sessions posters de doctorants sont également organisés et des prix pour les meilleurs posters seront décernés.

Ce cours se tiendra sur le campus d'Orsay
Amphitheatre Nelly Riguet, Institut Curie, Batiment 111, Centre Universitaire Paris Saclay, Orsay (Essonne)

Les conférences seront retransmises en direct via Teams.

Séminaire proposé par Marine Poupon,
Chargée de communication

Treatment resistance is a major challenge in cancer care. Beyond genetic changes, non-genetic changes affecting gene expression can drive intrinsic resistance, which are harder to study due to the responsive nature of the transcriptome. To tackle this, we developed ReSisTrace, a methodology that uses shared transcriptomic features of sister cells to predict cell states priming treatment resistance.

Initially, ReSisTrace was applied to a high-grade serous ovarian cancer cell line to reveal pre-existing resistant states to chemotherapy, targeted therapy, or innate immunity (Dai J. et al, Nature Communications, 2024).  In ReSisTrace, cancer cells are labelled uniquely with genetic barcodes and allowed to divide once so that each sister cell pair can be identified based on a shared barcode. Then single cell transcriptomes are analysed from half of the cells before the treatment, while treating the other half. Finally, analysis of the surviving cells enables the identification of the resistant lineages and tracing back their pre-resistant states via the sister cells analysed prior to the treatment.

Using this approach, we predicted small molecules that could reverse the pre-resistant states, and shift cells to states resembling transcriptomes of pre-sensitive cells. These drugs significantly sensitized cells to carboplatin, PARP inhibitor, or NK killing when used as pre-treatment  Now, we have expanded the method to a patient derived ovarian cancer organoid model. Even in this more heterogeneous and challenging context, we were able to identify a pre-existing chemoresistant state, and successfully target it with a pre-sensitising therapy, thus suggesting broad applicability of the method.  In summary, ReSisTrace reveals features of cells that will become resistant to treatments by coupling cell state and fate in sister cell resolution. It is widely applicable to identify and target pre-existing resistant cell states across cancer types and treatment modalities, including immunotherapies. Our final aim is to develop sequential cancer therapies to block resistance before it emerges.

Proteins in cells are not homogeneously distributed, but often localized to specific compartments, which may or may not be enclosed by membranes.  
Here I will first discuss the dynamic formation of membraneless compartments in the non-equilibrium environment of living cells and how this formation can be regulated, e.g. by kinases [1].  Then I will show how single-molecule FRET (smFRET) and tracking of biomolecules can be used to study conformational dynamics and time-resolved cellular localization in living cells [2]. Results with the transcription initiation factor TAF2 show that the same protein can be in different compartments and thereby have different functions [3]. For the heat shock protein Hsp90 we will determine how proteins may be recruited to different compartments and have different conformational dynamics.  
Altogether, smFRET has the potential to change our view on compartment-specific protein dynamics and therefore signalling within living cells.
 
[1] C. Lan, J. Kim, S. Ulferts, F. Aprile-Garcia, A. Anandamurugan, R. Grosse, R. Sawarkar, A. Reinhardt and T. Hugel, Nat. Commun., 14:4831 2023 (https://doi.org/10.1038/s41467-023-40540-2)
[2] A. Anandamurugan, A. Eidloth, P. Wortmann, L. Schrangl, F. Aprile-Garcia, C. Lan, R. Sawarkar, G. J. Schütz, T. Hugel, bioRxiv 2023 (https://doi.org/10.1101/2023.09.15.557875)
[3] T. Bhuiyan, P. K. Mendoza Sanchez, N. Arecco, J.  Kim, S. Nizamuddin, A. Prunotto, M. Tekman, M. L. Biniossek, S. Koidl, T. Hugel, S. J. Arnold, bioRxiv 2024, (https://doi.org/10.1101/2024.02.05.578926)