Cellular adhesion processes play a key role in the interaction of each cell with neighboring cells and with the microenvironment. They involve complex dynamics of the cytoskeleton and cell membranes. Disruptions in adhesion processes are associated with pathologies including cancer and osteoporosis.

Our team studies the cellular and molecular mechanisms that control cell adhesion and, in particular, the dynamics of membranes and the cytoskeleton. Our work allows us to understand how deregulations of these mechanisms contribute to the development of human diseases, such as cancer and osteoporosis. We wish to initiate the development of new innovative therapies. Our main axes are:

Cytoskeletal dynamics underlying the control of bone resorption

The cytoskeleton of the osteoclast, comprising in particular microtubules and actin filaments, has an essential role to ensure the adhesion of the cell to the bone and to maintain the bone resorption apparatus. This function is crucial to control osteoclast bone resorption activity, which is necessary to preserve bone health. Our recent work has shown that this cytoskeleton can also be used as a therapeutic target to prevent uncontrolled osteoclast activity, which is found in many metabolic, inflammatory or cancerous diseases. Our current work aims to understand how microtubules and actin filaments cooperate to ensure osteoclast adhesion to bone and to control its bone resorption activity.

Flotillins and tumor invasion

Flotillins are proteins that are overexpressed in many cancers, which favors the invasiveness of tumor cells and is associated with a poor prognosis for patients. Functionally, flotillins are essential to control the membrane trafficking of key proteins in tumor development. Our recent work has shown that membrane receptor trafficking, between the plasma membrane and intracellular compartments, plays a key role in cell response to microenvironment and matrix signals. We are currently seeking to understand the molecular mechanisms by which flotillins control membrane trafficking and how their deregulation leads to aberrant signaling and disruption of cell adhesion, which together promote tumor invasion in different types of cancers.

Cellular adhesion and bone formation

In particular, flotillins are involved in the formation of focal adhesions containing integrin b1 and in the recycling of this integrin. Integrin b1, a key player in cell response to mechanical signals, is essential for the formation and mineralization of bone matrix by osteoblasts. Our recent work has shown that integrin b1 controls vesicular trafficking in osteoblasts in response to matrix stiffness. Our current work focuses on the functional interaction mechanisms between integrin b1 and flotillins, and in particular their involvement in bone formation by osteoblasts.

To answer these questions we use different cell models: osteoblasts, osteoclasts, cells from various types of cancers (osteosarcoma, breast cancer…). We use different methodological approaches: advanced cellular imaging (live cell microscopy, electron microcopy, super resolution, optogenetics), in vivo models in mice or zebrafish and various techniques of genetic modification, biochemistry and cell signaling.

All these approaches allow us to address questions in fundamental cell biology with a focus on the understanding of human pathologies.

Le matériel génétique est le substrat de transactions telles que la transcription et la réplication, qui engendrent le risque de créer des lésions. De plus, l’ADN est exposé à des sources de dommages externes et internes. Dans tous ces cas, la cellule met en œuvre des mécanismes de surveillance et de réparation pour préserver l’intégrité du génome. Tous ces événements se déroulent dans le noyau de la cellule et, par conséquent, énormément d’efforts ont été consacrées à la compréhension de ces mécanismes nucléaires. Cependant, le noyau est enchâssé dans le cytoplasme et des recherches récentes commencent à mettre en lumière l’impact que les processus jusqu’ici considérés exclusivement comme cytoplasmiques peuvent avoir sur l’organisation, la maintenance et la dynamique du génome. L’objectif de notre équipe est d’élargir nos connaissances sur la manière dont les configurations nutritionnelles, les signaux environnementaux et les altérations métaboliques affectent ou même contrôlent le maintien de l’intégrité du génome. Pour aborder ces sujets, nous tirons parti de S. cerevisiae et des cellules humaines en culture en tant que systèmes modèles et utilisons une combinaison de Génétique, Biologie Moléculaire, Biochimie et de Microscopie à Fluorescence.

Nous analysons le rôle des isoformes de p53 dans des processus cellulaires associées à l’invasion tumorale : le mode de migration, la sénescence cellulaire et la formation de cellules souches tumorales. Un objectif majeur est de déterminer si certaines isoformes sont associées à l’agressivité tumorale et constituent de nouvelles cibles thérapeutiques. Dans cette optique, nous souhaitons identifier les programmes cellulaires qui contrôlent l’expression des isoformes de p53 lors de l’invasion cancéreuse et décoder les mécanismes par lesquels ces isoformes contrôlent l’invasion cancéreuse grâce à l’identification de leurs partenaires et de leurs cibles.

Nos études in vivo sont réalisées dans des cellules cultivées en 2D, mais également en 3D pour se rapprocher des conditions physiologiques des tissus. Nous combinons les analyses cellulaires (potentiel de cellule souche, vidéomicroscopie de cellules vivantes et xénogreffes murine) à l’analyse de tumeurs humaines et les analyses protéomique et transcriptomique à haut débit.

Asymmetric cell division is the main mode of division of stem cells and plays a central role in generating cell diversity during development. Indeed, during asymmetric cell division of polarized cells, biomolecules are asymmetrically segregated between daughter cells. The position of the mitotic spindle within the cell determines whether the cell will divide symmetrically or asymmetrically. Spindle positioning, in turn, depends on the interaction of astral microtubules (cMTs) with cortical factors. A complex network of proteins, such as non-motor microtubule-associated proteins (plus-end tracking proteins, +TIPs), kinesins, dynein and actin-interacting proteins, are involved in these interactions.
Budding yeast also divides asymmetrically and is used as a model organism to study asymmetric cell division. Spindle positioning in yeast depends on two genetically identified pathways: i) the dynein pathway that includes complexes of the microtubule-dependent motor dynein, and ii) the Kar9 pathway. Kar9 is the yeast functional equivalent of the Adenomatous Polyposis Coli (APC) tumour suppressor, a protein with a central role in spindle positioning from Drosophila to mammals. Dynein, Kar9 and APC homologues are universal mediators of spindle positioning during eukaryotic asymmetric division, but their regulation is poorly understood.

In the laboratory, we explore how cell cycle regulators modulate the temporal activation and dynamics of dynein and Kar9 complexes during spindle positioning in budding yeast. During their transport along microtubules and interactions with cortical proteins, these factors form highly dynamic protein complexes. Cyclin-dependent kinases control both the formation of these complexes and the coordination of their activity with other cytoskeletal events, such as chromosome segregation and cytokinesis. To understand the regulation of Kar9 and dynein complexes we use genetics to study their interactions. Using protein biochemistry, we analyse the Kar9/dynein complex composition and phosphorylation. Finally, we investigate complex dynamics in living yeast cells by time-lapse fluorescence imaging.