Département d’Oncologie Moléculaire Institut Paoli Calmettes, Marseille
“Profilage oncogénomique des cancers avancés dans les essais PANDORA et PERMED à l’IPC"
"Single cell transcriptomics and proteomics"
Résumé de la présentation : High-throughput, single-cell expression measurements enable discovery of gene expression dynamics for profiling individual cell types. The Chromium Single Cell Controller which is a dedicated instrument for single cell applications and features a simple and comprehensive workflow, enabling users to quickly and easily prepare single cell sequencing libraries in less than one workday.
With the unique ability to interrogate hundreds to millions of cells, the Single Cell Chromium Controller supports a variety of applications, including the existing Chromium™ Single Cell 3’ Solution, as well as a future product featuring to perform full-length sequencing of V(D)J segments from single B or T cells. The system is accompanied by Chromium Single Cell 3’ Reagent Kits with advanced chemistry and microfluidics consumables based on GemCode™ Technology and features full compatibility with the Illumina® HiSeq® 4000 and other HiSeq®, NovaSeq®, NextSeq® and MiSeq® sequencers.
Head of Artificial Intelligence and Gene Regulation, IGH, Montpellier
“Artificial Intelligence empowers transcriptomics but will ultimately cause its demise"
The seminar in short:
In my talk, I will show how simple information theory concepts such as entropy and information content allow scientists to better understand gene regulation in numerous types of disease. I will then demonstrate that recent advances in artificial intelligence approaches such as genetic programming and neural nets may be so powerful that they abrogate our need to understand these functions at all. Recent research in my team will show how AI allows us to explore sequencing data from cancer samples with no a priori and is more powerful than current approaches for classifying and predicting outcomes.
INSERM-U981 Institut Gustave Roussy, Villejuif.
"Collective epithelial-based metastases in colorectal carcinoma patients"
As a critical step in cancer progression and a challenge to patient treatment, tumour cell dissemination has been the subject of intense investigation across a range of model systems, in vitro and in animals. These studies have led to the assumption that the fatal progression of carcinoma is associated with a loss of epithelial architecture and polarity1-3 as single tumour cells escape from the primary tumour to reach secondary sites4,5. However, these studies have been performed using experimental model systems and the mechanisms driving metastatic spread in cancer patients remain under-investigated. Here, we collected and monitored over 50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastasis as it spreads to the peritoneum. This reveals a new mode of cancer dissemination. Large clusters of cancer epithelial cells displaying an inverted apico-basolateral polarity, which we term Tumour Spheres with Inverted Polarity (TSIPs), were observed throughout the process of tumour dissemination. We show that TSIPs form and propagate through the collective apical budding of hyper-methylated neoplastic tissues. Despite their inverted topology, TSIPs collectively invade extracellular matrices, paired patients¹ peritoneum explants and initiate metastases in mice xenograft models. Further, the presence of TSIPs in peritoneal effusions correlates with metastases burden and adverse patient prognosis. Thus, despite their having a robust epithelial architecture, TSIPs appear to drive the peritoneal dissemination of CRC, as well as other primary cancers, such as breast carcinoma. By applying cell biological methods to live primary cancer specimens, we provide an alternative conception of cancer dissemination that goes against the prevailing consensus and could not be anticipated from experimental model systems.
Department of Molecular and Translational Medicine, University of Brescia
"Stromal delivery of long Pentraxin-3 impairs FGF/FGFR-dependent tumor growth and metastasis"
The fibroblast growth factor (FGF)/FGF receptor (FGFR) system plays a crucial role in cancer by affecting tumor growth, angiogenesis, drug resistance and escape from anti-angiogenic anti-vascular endothelial growth factor therapy. The soluble pattern recognition receptor long-pentraxin 3 (PTX3) acts as a multi-FGF antagonist. In a recent study we demonstrated that local and systemic delivery of human PTX3 in transgenic mice driven by the endothelial specific Tie2 promoter inhibits tumor growth, angiogenesis and metastasis in heterotopic, orthotopic and autochthonous FGF-dependent tumor models. Moreover, NMR data and pharmacophore modeling of the interaction of a minimal PTX3-derived FGF-binding pentapeptide with FGF2 were used for the identification of the first small molecule chemical (NSC12) which acts as an orally active extracellular FGF trap with significant implications in cancer therapy. We are currently characterizing the role of PTX3 expression in different types of solid and hematological tumors.
Life Science Center, Vilnius University, Lithuania
'Targeting lipid rafts as a strategy against infection and cancer"
Short summary of the work:
Lipid rafts are membrane micro-domains that are enriched in cholesterol, sphingomyelin, sphingolipids and phospholipids. Their importance for living cells is underlined by their involvement in many processes including bacterial and viral entry, cardiovascular and prion diseases as well as cancer. Targeting lipid rafts is emerging as an innovative strategy to limit bacterial or viral infection and to increase the sensitivity to apoptosis of different types of tumours. Behind well-known cholesterol depleting agents (cyclodextrin) new compounds involved in cholesterol homeostasis were recently discovered. These potential drug candidates are capable to modify the lipid rafts composition and to alter the signalling platform associated with them. Multiple technologies including confocal microscopy to visualize lipid rafts, viability assays to determine the toxic effect of compounds on the cells, offer the opportunity to study in details the changes induced by this new class of cholesterol-targeting agents.
IGF, CNRS UMR5203, INSERM U1191, Montpellier
"Regulation by phosphorylation of two GPCRs targeted by antipsychotics"
Purdue University Center for Cancer Research, West Lafayette, In. USA
“Cancer-on-a-chip to study progression mechanisms and anticancer drug sensitivity”
The design of tissue-chips is gaining momentum because these engineered cell culture platforms provide highly controlled microenvironments for the study of normal and diseased tissues. I will discuss how tissue-chips can be used to recreate the organ geometry necessary for the full recapitulation of cell behavior, using the example of carcinomas that develop within ducts. Indeed, the curved environment of hemichannels confers mechanical constraints that influence drug sensitivity. So far, this system is surpassing other cell culture models for the assessment of drug efficacy at the cancer cell level, as shown with the example of triple negative breast cancer. Another use of tissue-chips is to create gradients of molecules in the microenvironment that are conducive to tissue heterogeneity responsible for cancer progression and drug resistance. We have designed a gradient-on-a-chip with which we demonstrated that increased matrix stiffness associated with breast cancer progression lowers the concentration at which progression promoting oxidizing molecules worsen cancer phenotypes. Throughout the seminar basic principles of tissue-chip design will be presented and the applications of cancers-on-a-chip for precision medicine will be highlighted.
IRIC, Université de Montréal, Qc, Canada
"Identification and preclinical validation of new therapeutic targets in liver cancer."
Séminaire dans le cadre des enseignements du M2 Cancer Biology ?
IGMM, CNRS Montpellier
"How do environmental cues control cell behaviour or fate decision programs? Learning from Rho and Ras transcriptional effectors."
Environmental cues such as growth factor, hormone, nutrient and cytokine concentrations are essential in regulating cell behaviour and differentiation processes. Cells integrate these external stimuli through signalling pathways to mediate their response. Aberrant signalling processes are a common feature of diseases such as cancer, so understanding them is critical for the development of therapeutic interventions. In our previous work, we have focussed on the Ras and Rho pathways, whose activity is disrupted in a large proportion of human cancers. The Ras pathway is instrumental in control of cancer cell proliferation, while the Rho pathway is a critical player in metastasis. The model we have used is the fibroblast serum response, a classical model for cell cycle re-entry and wound healing. The transcriptional response to serum is in its large part controlled by the Serum Response Factor (SRF). SRF functions in partnership with members of two families of signal-regulated cofactors: the MRTFs (myocardin-related transcription factors; MRTF-A, MRTF-B, and myocardin itself) and the TCF (ternary complex factor) family of Ets domain proteins (SAP-1, Elk-1, and Net). The MRTFs, which bind G-actin, respond to fluctuations in G-actin concentration induced by Rho GTPase, while TCF activity is controlled by Ras–ERK signaling. Investigating at the genomic scale the serum response, we have described how transcription and epigenetic rearrangement are regulated. We have defined the regulatory elements and genes that are regulated by Rho and Ras signalling pathways and explored how SRF and its coactivators modulate the circadian rhythm, the response to mechanical signals and control the balance between cell proliferation and invasion. In addition to soluble biochemical messengers, cells also need to respond to physical constraints i.e. external forces or mechanical cues such as stretch, compression and changes in the stiffness of the extracellular matrix (ECM). Although they are of critical patho-physiological importance, the molecular events elicited in response to mechanical cues have remained elusive. Indeed, during oncogenesis progression, the extracellular matrix (ECM) surrounding the tumour is stiffening due to matrix remodelling. It can arise from fibrosis or in response to tumour compression and cytoskeletal tension. Mechanosensation and tumour progression are paired: ECM stiffening supports the metastatic program and promotes cytoskeletal rearrangements required during cell invasion. Moreover, normal cellular differentiation has also been shown to be critically dependent on integration of mechanical cues. Mesenchymal Stem Cells (MSCs) are multipotent cells, which are able to differentiate into a variety of connective tissues. In this process, mechanical cues are determinant drivers of the lineage choice: the bone marrow is composed of discrete regions of variable matrix compositional properties, exposing MSCs to low tension conditions favour adipogenesis, while higher tensions favour myogenesis and the highest tensions drive differentiation to osteogenesis. Similarly, physical cues from the microenvironment regulate epidermal stem cell fate decisions. In that case, actin cytoskeleton rearrangement induces keratinocyte differentiation. However, while Rho and Ras signalling pathways have been identified in the response to matrix stiffness, how mechanosensation signals are transduced, integrated by the cell, how they impact on the transcriptional or epigenetic programs, what are the transcription factor networks involved apart from SRF/MRTF and YAP/TAZ and how such cues regulate cell behaviour are still open questions that I further aim to address.
INSERM U1015 Gustave Roussy, Villejuif/Université de Rome La Sapienza, Rome
"Intestinal microbiota and Escherichia coli involvement in inflammation and cancer"
Departement d'Hématologie, Hopital Saint-Louis et Université Paris Diderot, Paris, France
“Development of immunotherapy for the treatment of acute myeloid leukaemia”
IDIBELL Bellvitge Biomedical Research Institute, Barcelone
"Novel therapeutic opportunities for breast cancer treatment"
Centre de Recherche en Cancérologie de Toulouse, Toulouse
"Development of an anti-tumor associated macrophage antibody for cancer immunotherapies”
Among cellular components of the Tumor microenvironment (TEM), tumor associated macrophages (TAM) are modified macrophages educated by the tumor to favor its development. Being able to eliminate or deactivate these cells is a challenge today in anticancer therapies. We recently produced a new antibody specifically directed against human TAM. We chose the chronic lymphoblastic leukaemia (CLL) as model which is a malignant hemopathy with only 50% of complete remission and a deleterious effect of the treatment on the immune system of the patients. The resistance of the residual disease is due to the intrinsic properties of cancer cells but also to their close contact in lymph nodes with nurse like cells (NLC). We defined these cells as CLL’s TAM, infiltrating the lymph nodes and associated with the aggressiveness of the disease in a contact dependant manner. Target these cells would be a new therapeutic insight in cancer. NLC are easily produced in vitro by the culture of PBMC from CLL patients by the differentiation of monocytes in contact with CLL cells. After a mouse immunization with these NLC, we selected one antibody specifically targeting NLC (patent Inserm). This antibody called 6-25 does not bind to leukemic cells or healthy B and T lymphocytes and monocytes. Moreover, immunohistochemistry and immunofluorescence analyses of different human tumors proved that our antibody can target different TAM. In parallel, we found that the target of the 6-25 mAb is the sideroflexin 3 (patent Inserm). The advantage of our anti-SFXN3 antibody is the specificity of TAM targeting with a promising future in anticancer therapies.
IRIC, Université de Montréal, Qc, Canada
"Targeting estrogen receptor signaling in breast cancer treatment: lessons from omics approaches and live cell biosensors"
Séminaire dans le cadre des enseignements du M2 Cancer Biology
IGMM, CNRS, Université de Montpellier
"Chromatin looping as a regulator of normal and pathological erythropoiesis"
“Targeting GMP synthesis reveals a hierarchy of p53-cell cycle checkpoints in CRCs”
Université Libre de Bruxelles
"A role of SHIP2 in metastasis of breast cancer“
NCI/NIH, Bethesda, Md., USA
"Non-camptothecin TOP1 inhibitors 1st and 2nd generation development"
Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA approved drugs: topotecan and irinotecan, the derivatives of camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel non-camptothecin TOP1 inhibitors in clinical trial (phase 1). They overcome camptothecin limitation such as chemical instability, resistance by drug efflux, short plasma half-life or severe diarrheas. To further improve their metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines LMP517, LMP135, and LMP134.
In order to build the rationale for phase 2 clinical trials for the indenoisoquinolines, we have taken two approaches. First, CellMinerCDB (http://discover.nci.nih.gov/cellminercdb) was used to mine the cancer cell lines genomic databases. And second, because TOP1-mediated replication DNA damage is repaired by homologous recombination (HR), we tested “synthetic lethality” in HR-deficient (HRD) cells. We also tested the induction and stability of TOP1 cleavage complexes (TOP1cc) by the new fluorinated compounds and the induction and persistence of DNA damage they generate compared to their parent compound.
Genomic database mining revealed that a dominant drug response determinant is Schlafen 11 (SLFN11), a putative nuclear helicase/nuclease that kills cells undergoing replication stress. We also found that BRCA1-, BRCA2- and PALB2-deficient cells are 3 to 5 times hypersensitive to the indenoisoquinolines 1st generation. The fluoroindenoisoquinolines induced TOP1cc and DNA damage at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. LMP135 showed greater antitumor activity than topotecan in small-cell lung cancer cell H82 xenografts. Genomic database also showed that the activity of the fluoroindenoisoquinolines was mostly correlated with camptothecin derivatives and the parent indenoisoquinolines, consistent with TOP1 targeting.
Our results provide a rationale for Phase 2 indenoisoquinolines clinical trials with the indenoisoquinolines in HR-deficient cancers and for measuring Schlafen 11 (SLFN11) as a clinical response determinant. And it also shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1.
MacCallum Cancer Center, Melbourne, Australia
"Novel Strategies for Restoring Tumour Suppression to Treat Cancer"
"Antibody Functional Diversity as the Key to Unlocking Novel Target Biology"
Argenx is a clinical-stage biotechnology company using its suite of differentiated technologies to engage with academic centers of excellence to access exciting, novel targets where proof of concept in disease models is yet to be shown. Through its so-called Innovative Access Program, argenx brings its proprietary antibody technologies and know-how to collaborations with target biology specialists, enabling rapid progress into translational studies and creation of novel antibody candidates with therapeutic product potential.
Plus d'informations sur www.argenx.com/en-GB/content/argenx-in-short/2/
Laboratoire Réactions et Génie des Procédés (LRGP), UMR CNRS 7274, Université de Lorraine
"Intensification et maîtrise des procédés de production de biomédicaments"
La demande en forte croissance des biomédicaments produits par cellules animales impose d'intensifier les capacités de production. Ces produits incluent de nombreuses biomolécules, dont en particulier les anticorps recombinants, ainsi que des cellules utilisées elle-mêmes pour leur intérêt thérapeutique. Cependant, l'extrapolation de l'échelle de la boîte de culture à celle du bioréacteur reste loin d'être une évidence. Le défi consiste à comprendre, maîtriser et contrôler ces bioprocédés par une approche pluridisciplinaire, en vue d'obtenir des performances optimales, et ce, en dépit de l'environnement contraignant auquel sont soumises les cellules. Une vue d'ensemble des spécificités de ces procédés et des recherches en cours sera proposée et illustrée par des exemples.
Plus d’informations sur http://lrgp-nancy.cnrs.fr/spip.php?rubrique74
GIGA-CANCER, Université de Liège, Belgique
"Targeting glycolysis-derived oncometabolites as a promising anti-cancer strategy”
Metabolic adaptation of cancer cells is recognized as a main hallmark of cancer. Tumour cells are notably characterized by an increased glucose uptake and a high glycolytic flux also known as the “Warburg effect”. One underestimated consequence of this glycolytic switch is the production of methylglyoxal (MG). MG is a highly reactive dicarbonyl that reacts with nucleic acids and proteins to form advanced glycation end products (AGEs), thus creating a dicarbonyl stress. The non toxic accumulation of MG and AGEs adducts are implicated in many pathological situations including diabetes, heart disease, neurodegenerative disease, ageing and cancer. Dr. Bellahcène’s team got interested since 2013 in the study of dicarbonyl stress in the development and progression of cancer. Upon MG stress, breast cancer cells show enhanced growth and metastatic potential in vivo that is efficiently reversed using carnosine, a natural MG scavenger. Given the explosion of interest and information on cancer metabolism, exploring the mechanisms regulating the levels of MG oncometabolite will be determinant for understanding tumor biology and improving cancer therapy.
INSERM U1176, Hémostase, Inflammation et Thrombose
"Application of classic antibodies and nanobodies in hemorrhagic disorders"
The treatment of hemorrhagic disorders like hemophilia and von Willebrand disease is largely dependent on replacement therapy using the missing protein. Such therapies are expensive, require frequent intravenous injections and are (in case of FVIII-replacement therapy) associated with the development of inhibitory antibodies in up to 30% of the patients. Over the last decades, alternative approaches have been or are being developed, some of which are based on the therapeutic use of antibodies or antibody-based proteins. Also in our laboratory, we have developed antibody-based therapies, some of which being advanced candidates for clinical development.
One example regards antibody LTX-508, a monoclonal antibody that binds to von Willebrand factor (VWF). VWF is a multimeric protein responsible for the recruitment of platelets. In patients that receive mechanical circulatory support (as in LVAD or ECMO), VWF is excessively degraded. Up to 50% of these patients manifest bleeding complications, which are associated with prolonged hospitalization and increased mortality. Antibody LTX-508 aims to reduce degradation of VWF under these conditions. Another example relates to a FVIII-nanobody fusion protein, designated FVIII-KB013bv. In this protein, FVIII is fused with a nanobody directed against its carrier protein VWF. The presence of the nanobody increases its affinity for VWF 25-fold, and this increased affinity is associated with a two-fold prolonged half-life and, more importantly, a 7-fold reduction in the number of mice that develop inhibitory antibodies against FVIII. Finally, we have also developed nanobodies against antithrombin, a main inhibitor of the coagulation cascade. The nanobodies interfere with antithrombin activity, and can be used to restore the hemostatic balance in hemophilia A and B. In vitro and in vivo data confirm that such nanobodies can correct for the absence of FVIII or FIX. The advantage of such nanobody-based therapy is that these antibodies can be given both subcutaneously and intravenously, while their stability may allow storage at room temperature rather than 4?C.
Institut de Recherche en Immunologie and Cancérologie (IRIC), Université de Montréal, Canada
"Signalization controlling cell morphogenesis: From fly mitosis to human cell motility"
Institut pour la Recherche sur le Cancer de Lille, Université de Lille, U900 INSERM
"Tumor dormancy: quiescence or equilibrium?"
Tumor dormancy occurs when cancer cells are present but the tumor does not grow. Following treatment, patients may enter complete remission in which persistent cells represent the minimal residual disease (MRD). Experimental models and clinical data suggest that the absolute quantity of this MRD is extremely low. Very few cancer cells can persist for years or decades, and induce late relapse, sometimes decades after diagnosis. A key question is whether these long-term persisting cells remain in a truly quiescent state or if a stable equilibrium establish between residual cancer cells and factors of destruction, including treatments or immune response. Although several experimental and clinical data indicate that dormant tumor cells may remain in G0 in specific tumor micro-environments, other results show clonal evolutions, epigenetic modifications, and active suppression of immune response, suggesting that dormancy may be also an active process.
Professor of Pediatrics and Genetics, Stanford University, Ca., USA
"Intra- and Inter-tumoral heterogeneity in small cell lung cancer"
Department of Biology, Stanford University, Ca., USA
"A Novel Protein Acyltransferase Complex Involved in Cancer Cell Signaling and Death"
Immunité et Cancer, IRCM, Montpellier
"In bed with cells: how mass cytometry and imaging may reveal the intimate in-situ cell-cell interactions"
Center of Immunology, Medical University of Hamburg-Eppendorf, Allemagne
"Nanobodies from transgenic mice"
Llamas and other camelids produce unusual antibodies composed only of heavy chains. The variable domains of these antibodies (designated VHHs or nanobodies) have been shaped by evolution for high solubility and stability, independent of a partner VL domain. Nanobodies have emerged as promising therapeutics in various disease areas including heamtology, oncology, inflammation and infection. With their long CDR3s, nanobodies can reach hidden epitopes that are not accessible for conventional antibodies. In order to facilitate the generation of nanobodies for biomedical applications, we have generated nanobody-transgenic mice. Immunization of these mice induces antigen-specific heavy chain antibody responses with efficient somatic hypermutation and class switch. These mice thus provide a flexible new platform for generating innovative nanobody-based biologics. They also provide a basis for genetic modification of nanobodies and the generation of designer nanobodies.
Préprotéine converstases, invasion tumorale et métastases, U1029 INSERM, Bordeaux
"Protein maturation in colorectal cancer and immunotherapy"
CRG, Barcelona, Espagne
"Investigating the Functional Implications of Arginine Citrullination"
Centre de Recherche en Cancérologie de Marseille
"Antibody targeting of pathological B cell protective niches"
It is now clear that the bone marrow microenvironment plays an essential role in B cell differentiation. Indeed, mesenchymal and endothelial cells contribute to a protective microenvironment called hematopoietic niches that secrete specific factors and establish direct contact with developing hematopoietic cells. In the laboratory, we identified distinct niches specific for normal pro-B cells and pre-B cells respectively. Importantly, resistance and relapse in the case of B cell acute lymphoblastic leukemia (B-ALL), pathological equivalent of differentiating B cells, are also partly related to protective cues transmitted by stromal cells.
Our goal is to define the molecular mechanisms involved in lympho/stromal interactions and thus develop therapeutic antibodies targeting the interactions between pathological B cells and their protective microenvironment. In that purpose, we developed an interactome bioinformatics pipeline allowed the identification of ligand/receptor pairs involved in B cell specific interactions with mesenchymal cells. This system allowed the identification of a new ligand/receptor pair involved in pro-B cell retention in their developmental niche. We further extended our knowledge about normal BM niches to pathology and found that factors expressed by normal stromal cell niches can play a crucial role in leukemic B cell growth. These different aspects and the similarities of hematopoietic niches between species will be discussed.
Sorbonne Université, Paris
"Gut microbiota ecology and host immunity in adulthood and neonate life"
A race between microbiota installment through colonization and maturation of host immunity dominates neonate life. Indeed, man is colonized immediately upon birth by environmental microbes of primarily maternal origin. Vertical transmission of immunity through breastfeeding allows the child to jump-start the immune maturation process and cope with the massive ongoing microbial invasion. Initial colonization and transfer of maternal immunity through breastfeeding are believed to impact infant health at short- and long-term by conferring protection from infection and potentially resistance to metabolic and allergic diseases. I will discuss how host immunity, in particular microbe-specific secretory IgA, regulates the composition of the gut microbiota in an antigen-specific manner (Fadlallah et al. STM 2018) and how microbe-specificity of intestinal and systemic immunity converge (Fadlallah et al. JACI 2019). I will outline mechanisms implicated in host-microbe regulation and finally I will introduce our attempts to elucidate the effects of these interactions in newborns. Potential clinical links with obesity and allergic disease as well as diagnostic and therapeutic implications will be discussed.
Université de Zurich, Suisse
« Deep profiling of tissue ecosystems with Imaging Mass Cytometry »
Team ‘Environment & INteSTinal Epithelium INteractions’ Institut de Recherche en Santé Digestive, INSERM u1220, INRA u1416 CHU Purpan, Toulouse
Intestinal Epithelium & Environment Interactions : Roles in Inflammation & Tumorigenesis
L’épithélium intestinal représente une barrière fonctionnelle essentielle pour notre organisme en permettant l’absorption des nutriments, des sels et de l’eau tout en assurant une protection contre les agents pathogènes. Afin d’assurer ces fonctions, les cellules de la muqueuse intestinale se renouvellent tous les 5 jours, soumettant le tractus digestif à un stress important dans le contrôle de la prolifération, la différenciation et l’organisation cellulaire de l’épithélium intestinal. Le renouvellement intestinal est étroitement contrôlé et dépend notamment de l'organisation spatiale des signaux émanant des cellules mésenchymateuses de soutien, en particulier les fibroblastes gainant la crypte et soutenant l’épithélium intestinal. L’homéostasie, et donc l'intégrité de l’épithélium intestinal, est constamment mise à l’épreuve par les facteurs environnementaux ‘extérieurs’ provenant de la lumière intestinale (additifs alimentaires, composés nutritionnels, microbiote…) ou ‘intérieurs’ (stroma, prédisposition génétiques…). Les facteurs environnementaux favorisant et/ou aggravant l'inflammation colique ou affectant le processus de renouvellement des cellules épithéliales sont une source majeure de préoccupation. En effet, toute altération de l’homéostasie intestinale va intervenir dans la mise en place des maladies inflammatoires chroniques de l’intestin (MICI) et la transformation tumorale. Les deux principales formes de MICI sont la maladie de Crohn (MC) et la rectocolite hémorragique (RCH). L’une des complications majeures des MICI est le cancer colorectal. D’autre part, le cancer colorectal sporadique (CRC) est la 3ème cause de mortalité par cancer dans les pays industrialisés. Nos projets de recherche, associant des approches morphologiques, fonctionnelles, pharmacologiques et microfluidiques sur des primocultures cellulaires en 3D d’organoïdes colorectaux et de fibroblastes, étudient l’impact environnemental (‘extrinsèque/luminal’ ou ‘intrinsèque/stromal’) sur la physio(patho)logie de l’épithélium intestinal, le développement du processus inflammatoire et la carcinogénèse.