Our bodies are the product of communication and cooperation between several tens of billions of cells. Cancer is a disease of the cell, caused by an impairment in its communication mechanisms and responses to the signals it receives. Researchers are studying the development of organisms and the function of individual cells, in isolation or in their natural environment within tissue or during interaction with the nervous or immune systems. These studies are crucial for understanding tumor formation and development. If we analyze cell proliferation, survival and migration, and impairments in these phenomena in cancerous cells, we can shed light on how cancerous cells develop. By identifying and characterizing key molecules controlling these phenomena in normal cells, our researchers will be able to pinpoint the biomarkers for the different stages of cancer and improve early diagnosis of the disease. Thanks to collaboration with chemists and structural biologists at the Institut Pasteur, new pharmacological compounds can be developed to block these impairments in cancerous cells.
Department of Cell Biology & Infection
The maintenance of cell identity and how it is subverted in cancer are essential questions in biology and medicine. Cell identity is dictated by specific gene expression programs mediated and reinforced by epigenetic processes. This unit is interested in the epigenetic and cellular mechanisms underlying the development of human cancers with a particular emphasis on the chromatin role played by the post-translational modification by SUMO, with a vision toward targeting this druggable pathway for cancer treatment.
Cytokinesis is the last step of cell division and leads to the physical separation of two daughter cells. Failure in cytokinesis results in the formation of genetically unstable tetraploid, then aneuploid cells, which promotes tumorigenesis in vivo. Importantly, it is sestimated that 40% of human carcinomas are derived from tetraploid cells, likely due to cytokinesis failure. Araud Echard’s lab currently works identifying the complete set of proteins essential for cytokinesis in human cells. They recently identified a tumor suppressor gene playing a role in normal abscission, the final step of cytokinesis. They now aim at understanding how abscission is monitored by a molecular pathway termed the abscission checkpoint, also called “NoCut checkpoint“ that prevents the formation of tetraploid cells in case of chromosomes fail to properly segregated between daughter cells.
Mechanisms of tumor cell migration and tumor invasion
Cancer cells are characterized by their increased proliferation and also by their invasive capacity which allows the tumor to spread and eventually leads to metastasis. The Cell Polarity, Migration and Cancer unit aims at identifying the key alterations that are responsible for cancer cell migratory properties. The team essentially focuses on glioblastomas which is the most frequent and invasive brain tumor, observed in adults and also in children. The team projects focus on two major aspects of cell migration:
1- The control of cell polarity and the establishment of a front-to-rear axis. Cancer cells frequently display an alteration of polarity which during migration is reflected by a less directed, less persistent migration. Characterizing the molecular alterations responsible for the perturbed polarity in these cells could be used to identify invasive tumors
2- The cytoskeletal rearrangements. The cytosqueleton forms intracellular filamentous networks which are at the core of cell migration by contributing to cell adhesion, cell protrusion, contraction and traction forces. The scientists are investigating the specificity of the tumor cell cytoskeleton in order to identify therapeutic target that will block tumor cell invasion.
Role of autophagy in cancer
Autophagy is a pivotal recycling pathway in cells. Its relationship to cancer is ambiguous and not entirely understood. On the one hand, autophagy is known to support the malignant degeneration of cells and the growth of KRAS driven cancers. On the other hand, autophagy promotes genome integrity and thus protects from malignant degeneration. Furthermore, autophagy plays important functions in cancer stem cells. The Thomas Wollert’s team investigates molecular principles of autophagy with a focus on pluripotent cells to reveal insights into the contribution of autophagy and its regulation in stemness in health and disease.
Understanding the role of tunneling nanotubes (TNTs) in tumor networking, heterogeneity and resistance to therapy.
Glioblastoma and neuroblastoma are well characterized for tumor heterogeneity and ability to transdifferentiate following therapeutic treatment, which results in therapy resistance and development of a more aggressive phenotype. This team hypothesizes that TNT-like structures have a major role in the establishment of their heterogeneity and progression and might be instrumental for their treatment. Thus by using a multidisciplinary approach combining cell biology, quantitative imaging and transcriptomic, our major aim is to evaluate the participation and consequences of TNT-based communication into these cancer’s networking.
Department of Computational Biology
Understanding ovarian tumor heterogeneity
Even though most ovarian cancer patients initially respond well to surgery or chemotherapy, most unfortunately relapse due to the presence of — sometimes few — drug-resistant cancer cells. As part of the cross-disciplinary HERCULES consortium, this team aims to elucidate the different molecular bases of this resistance, and to develop new analytical strategies to combat resistance on the basis of an understanding of patient and tumor heterogeneity. Their work builds on data-driven, computational models of resistance that are informed by novel technologies, such as single-cell transcriptomics.
Department of Developmental & Stem Cell Biology
Cellular quiescence and cancer (NSC quiescence control mechanisms and glioblastoma)
This team is focusing on the molecular mechanisms controlling neural stem cell (NSC) quiescence in vivo. Its experimental model is the adult brain of the zebrafish, which is enriched in quiescent NSCs. They identified several molecular pathways promoting NSC quiescence, notably Notch3 signaling and a nuclear mechanism involving microRNA-9, which both appear upregulated in glioblastoma stem cells. They also provided evidenced for the existence of quiescence sub-states, which remain to be molecularly identified, and linked with the specific quiescence status of cancer stem cells. They address these issues in collaboration with M. Gabut (CRCL, Lyon) by conducting parallel scRNAseq and functional analyses in NSCs in vivo and in glioblastoma stem cells in vitro, cultured as “tumospheres” or “tumorganoids”.
Acquired drug resistance is a major limitation for successful treatment of cancer.
Drug resistance is facilitated by several mechanisms including: drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition (EMT). This team proposes to dissect the evolution of drug resistance by charting and integrating genome-wide data sets of drug-resistant and sensitive cancer cell lines and patient samples. Their overall goal is to predict chemotherapy resistance, understand the gene-regulatory mechanisms that lead to resistance and devise potential treatment solutions.
Cell competition and its role in pre-tumoral cell expansion
Recent advances in single cell sequencing have revealed the strong heterogeneity of tumours and the essential role of the microenvironement in tumour progression. This includes competitive interactions between the tumoural cells and their neighbours and the competitive interactions within the tumours between clonal populations. While several theoretical works have suggested that those interactions will influence the growth of tumours and the emergence of drug resistant populations, the characterization of the molecular basis of such competitive interactions are still lacking. The team uses a combination of quantitative experiments in Drosophila and simulations to understand how mechanical stress contribute to such competitive interactions between pretumoural cells. A better understanding of the conditions allowing mechanical competition and the pathways involved in such interactions may help to better adapt cancer therapy and avoid the expansion of drug resistant populations.
Crosstalk between cellular senescence and cellular plasticity during tumorigenesis
Recent studies revealed that certain cancer cells are remarkably plastic, which contributes significantly to the cancer heterogeneity and resistance to therapy. How cellular plasticity is induced in cancerous cells is poorly understood. Cellular senescence is a form of stress response characterized by a stable cell-cycle arrest and is an essential tumor suppression mechanism, while the accumulation of senescent cells in the tumor could further promote tumorigenesis. The team proposes that senescence provides critical signals to induce cancer cell plasticity. Elucidating the interplay between cellular senescence and plasticity in tumorigenesis will shed new lights on various aspects of cancer biology, including the initiation, progression and metastasis.
How transcription factors regulate the epigenomic landscape and orchestrate the behaviour of regulatory networks under different environmental constraints?
Many cancer cells are “transcriptionally addicted”: their proliferation and survival strictly depends on transcription factors (TFs). Yet, during mitosis the chromatin is modified, condensed and re-arranged, leading to the dismantlement of TF-based gene regulatory processes. How do then cancer cells rapidly restart transcription after mitosis? Thanks to a label from the Ligue Contre le Cancer, we are studying the possibility that mitotic bookmarking processes based on the ability of certain TFs to mitotically bind its targets enable the rapid jumpstart of transcription after mitosis.
In vivo analysis and manipulation of an invasive brain tumour
Fast amplification and high invasiveness make brain tumours very aggressive. The cancer stem cells they contain are able to disseminate and re-initiate the tumour. These cells act as super-competitors, equipped to both destroy and hijack healthy cells, ultimately creating a cellular niche beneficial to tumoural growth and invasion. How the tumour remodels the healthy tissue to its needs is currently very poorly understood. This team’s project aims to decipher the core cellular mechanisms supporting these interactions, taking advantage of a genetically amenable, simpler and fully in vivo model, the fruit fly. They are especially focusing on the role of glia and blood-brain barrier populations in the dissemination process.
Cancer cachexia and muscle stem cells
This unit will investigate metabolic variations and asymmetric cell divisions of stem cells to identify key regulators of stem cell self-renewal and commitment in normal mice and cachexia. Cancer cachexia, which accompanies a variety of cancer types and results in diminished quality of life, can be considered as a metabolic disease that is mainly caused by reduced energy intake and metabolic activity. Two major objectives define the program of the scientists:
1) They will assess the metabolic requirements of myogenic cells in young and aged normal and cachexic mice. They will use this information to identify factors that confer resistance of certain muscles to cachexia;
2) Genes that have tumor suppressor function have been shown to regulate asymmetric cell divisions. They will therefore investigate in detail how asymmetric cell divisions contribute to self-renewal of muscle stem cells. They will then examine how their genetic and epigenetic properties are altered during regeneration in normal and cachectic mice.
Department of Genomes and Genetics
Genetics of quiescence (Génétique de la quiescence)
The cancer stem cell CSC model suggest that cancer arise from few mutations into an adult stem cell or more differentiated cell types that can gain mitotic potential in order to clonally expend. However, when and how those mutations are generated is not fully explain. The Benoit Archangioli’s team is working on the genetic of quiescence using Schizosaccharomyces pombe as a model organism and described the mutational rate and spectrum in this non-proliferating state. They recently isolated during quiescence a novel class of long-term survivors. A group of 9 mutants in the stress/mitogen activated protein kinase (S/MAPK) pathways known as oncogenes or tumor suppressor can reach 10% to 50% of an aged clonal population. They found that these mutant strains are able to exit quiescence much faster than the wild-type. This project might help to understand the logic of some metastatic relapse and reactivation.
HBV integration in hepatocellular carcinoma cancer cells and 3D genome organization
Department of Immunology
Importance of the tumor suppressor Adenomatous Polyposis Coli (APC) in anti-tumor immunity
Adenomatous polyposis coli (APC) is a tumor suppressor gene whose mutations are associated with Familial Adenomatous Polyposis and colorectal cancer. APC is involved in cell growth, differentiation, migration and death, controlling intestinal epithelial cell homeostasis. However, the role of APC in the immune cell functions key for antitumor immunity is ill defined. These findings on human CD4 T lymphocytes and APC mutant mice underscore the importance of APC in T lymphocyte activation leading to cytokine production, and in regulatory T cell (Treg) differentiation and anti-inflammatory function in the intestine, which may be of importance for the control of colorectal cancer. The researchers are currently exploring whether APC also modulates other immune cells, as cytotoxic T cells (CTL) or natural killer cells (NK cells), impairing their differentiation, migration, tumor infiltration and/or capacity to kill tumor cells, thus reducing anti-tumor defenses in patients.
DNA repair regulation and maintenance of genome integrity
DNA double-strand breaks (DSBs) are toxic cellular lesions that must be efficiently repaired to maintain genome stability and prevent cancer. Cancer cells frequently harbor somatic mutations leading to defective DNA repair causing genomic instability and promoting tumor onset and evolution. Defective DNA repair can also be therapeutically exploited as DNA repair deficient tumor cells, but not healthy cells in normal tissues, rely on compensatory pathways to survive endogenous or cancer therapy-related genotoxic stress. Although promising and recently exemplified with the use of PARP inhibitors for cancer treatment, therapeutically exploiting DNA repair is still in its infancy and its success will rely on our deep knowledge of complex DNA damage response mechanisms, a major focus in this laboratory. Specifically, the researchers study physiological immune receptor gene recombination processes in lymphocytes to unravel general DNA repair regulation, understand the origin of somatic mutations in cancers and ultimately identify new therapeutic opportunities. They currently work on the following projects:
1) Deciphering DSB repair regulation in lymphocytes through genetics and proteomics
2) Characterization of novel DNA repair genes implicated in cancer therapy resistance
3) Understand the origin of somatic structural variations in cancer genomes
Department of Structural Biology and Chemistry
The recent observation that nanobodies could cross cell membranes and bring cargos inside the cells also suggest that the targeting of an intracellular epitope should be feasible. This is why this team will develop intracellular nanobodies detecting specific nuclear factors in live cells allowing the simultaneous detection of transcription and intense replication stress. Transcription will be monitored with nanobodies developed against phosphorylated C-terminal domain (CTD) of the large subunit of Pol II (RPB1) (markers of chromatin bound and elongating Pol II), or against non-phosphorylated CTD (a marker of total nuclear Pol II), and the severity of replication stress will be monitored by nanobodies raised against gamma-H2AX and hyper-phosphorylated RPA.
Department of Virology
Jean-Pierre Vartanian / Simon Wain-Hobson
Somatic DNA mutator enzymes targeting in Liver Cancer
Cancer genomics has shown beyond doubt that cancer is a mutational process. The only surprise is the sheer numbers of mutations and rearrangements – up to 1.5 million mutations in a cancer genome. These mutations are frequently associated with a molecular footprint that helps link them to the mutagen. What are the sources of these mutations? The unit was the first to show that the human genome encodes two DNA mutator enzymes that can turn on chromosomal DNA. These mutator enzymes are called APOBEC3A and APOBEC3B and leave a characteristic and unmistakable mutational footprint in a sizeable fraction of cancer genomes. Mutations are remorsely accumulated by hundreds of successive waves of mutation spread out over several decades.
The team will identify this ongoing mutational process in pre-tumorous tissue. As hepatocellular carcinoma is generally preceded by cirrhosis. Cirrhotic tissue at different stages of advancement with respect to the moment of infection by Hepatitis B virus will be studied. The study will demonstrate that an end stage HCC reflects the growth of a liver cell that got into the mutational fast lane and outgrew other genetically wounded cells that accumulated mutations less quickly. This knowledge should help understand resistance of the cirrhotic liver to drug and immunotherapies for somatic mutations change biologic processes impacting complex protein networks. The study will be particularly relevant for all diseases involving chronic inflammation. We expect that to be far more somatic mutation that hitherto recognized and should bear light on the ageing process itself.