The fate of cells is established through the integration of tightly regulated instructive signals during embryogenesis and in adulthood. Qualitative and/or quantitative unbalance of signalling levels leads to degenerative diseases or cancer. Our team’s goal is to understand what determines and modulates a cell response to instructive signals, leading to diversify cell behaviours and features in developmental and pathological processes. Ultimately, we aim at uncovering strategies to modulate these signalling mechanisms in order to design targeted therapies.

FOR BEGINNERS

Developmental processes are finely regulated by a concert of signalling pathways that determine how cells must behave. Activation of instructive signals is tightly controlled in healthy adult tissues.  In contrast, uncontrolled signalling in susceptible cells can cause pathological events such as cell degeneration, cancer, and cell resistance to anticancer therapies. Conversely, reactivation of “developmental” signalling circuits frequently occurs in tissues undergoing degenerative processes as an attempt to contrast them.
Our team is interested in understanding how distinct “messages” are integrated to instruct cells during embryogenesis and how their alteration causes diseases. We use the mouse as an animal model to recapitulate developmental and pathological events (neurodegenerative diseases and cancer) and to test the effectiveness of novel therapies. Our research has two major aims :
1) Uncovering novel cooperative mechanisms underlying the evolution of normal cells towards tumorigenesis.
2) Elucidating the impact of novel mechanisms regulating the biology of stem cells for their use in regenerative medicine.

FOR SPECIALISTS

We aim at uncovering how convergent instructive signals cooperate to regulate the fate of cells. This question is addressed by using two biological contexts : the transition of healthy cells towards tumorigenesis and the regulation of self-renewal versus differentiation of stem cells. By applying an interdisciplinary strategy, our research is focussed on two axes:

1) Signalling cooperation in tumorigenesis by RTKs.

Modeling human tumors in mice in combination with genome-wide screening enables tracking cancer molecular mechanisms with great precision. This allows uncovering the compatibility between distinct signals, their cooperative outcomes, their interconnecting “signaling nodes”, their functional requirement in the oncogenic program, and the effectiveness of novel molecular therapies. We designed strategies to model the action of oncogenic receptor tyrosine kinases (RTKs) in vivo. In particular, we have generated transgenic mice that allow conditional “enhanced Met” expression and highlighted a sensitiveness of distinct cell types to enhanced Met signalling levels. We are currently applying this genetic model for integrative research to discover cooperative mechanisms underlying tumorigenesis by enhanced RTK signalling. This is achieved by combining genomic screens with bioinformatics, human data bank, and functional assess of outcomes in vitro and in vivo.

2) Signalling network crosstalk uncoupling tumorigenicity from therapeutic properties of human induced pluripotent stem cells.
Stem cell self-renewal and differentiation depend on a dynamic interplay of cell-extrinsic and intrinsic regulators. The perception of the right amount of signal and at the right time establishes whether stem cells maintain self-renewal properties or undergo cell differentiation. Recent breakthroughs in stem cell research have generated tremendous hope for the therapeutic potential of stem cells to treat degenerative diseases characterized by the progressive loss of distinct subtypes of cells. Induced pluripotent stem cells (iPSCs) appear the most promising candidate for successful cell transplantation in clinic. However, a major concern for the widespread therapeutic application of iPSCs remains the intrinsic properties of pluripotent stem cells to generate teratomas upon in vivo transplantation. This is due to a protracted proliferation and inefficient differentiation of stem cells once implanted in host tissues. We have demonstrated that the “fate” of stem cells depends on the action of morphogen regulators such as Glypican4 present on the cell surface. In particular,
Glypican4 down-regulation orients stem cells towards an accelerated and efficient differentiation. Strikingly, Glypican4 modulation not only enhances stem cell differentiation efficiency, but also overcomes tumorigenicity. Using transcriptome’s outcomes, we are delineating the underlay molecular mechanisms that uncouple tumorigenicity from pluripotent differentiation potential. Intriguingly, Glypican4 modulation permits stem cells to acquire a dopaminergic neuronal fate and to counteract motor deficits in Parkinsonian rat models. We are currently assessing the potential application of these findings for Parkinsonian’ disease therapy by using human iPSCs.