Signalling networks for stemness and tumorigenesis
Group leader : F. Maina
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.
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.
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.
June 6th, 2017
A Phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of non-oncogenic RTKs
October 9th, 2016
Coordination of signalling networks and tumorigenic properties by ABL in glioblastoma cells
June 17th, 2014
Reducing Glypican-4 in ES Cells Improves Recovery in a Rat Model of Parkinson's Disease by Increasing the Production of Dopaminergic Neurons and Decreasing Teratoma Formation.
June 9th, 2013
Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy.
December 1st, 2012
Met acts through Abl to regulate p53 transcriptional outcomes and cell survival in the developing liver.
September 1st, 2012
Modulating Glypican4 suppresses tumorigenicity of embryonic stem cells while preserving self-renewal and pluripotency.
January 1st, 2012
Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures.
October 1st, 2011
Abl interconnects oncogenic Met and p53 core pathways in cancer cells.
August 3rd, 2011
Pool-specific regulation of motor neuron survival by neurotrophic support.
March 17th, 2011
Enhanced neuronal Met signalling levels in ALS mice delay disease onset.
September 15th, 2010
Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons.
May 1st, 2007
Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner.
April 1st, 2007
Met acts on Mdm2 via mTOR to signal cell survival during development.
August 28th, 2013
Met signaling in cardiomyocytes is required for normal cardiac function in adult mice.
August 23rd, 2013
Strategies to Overcome Drug Resistance of Receptor Tyrosine Kinase-Addicted Cancer Cells.
February 25th, 2013
Analysis of c-Met kinase domain complexes: a new specific catalytic site receptor model for defining binding modes of ATP-competitive ligands.
July 15th, 2012
'Click' synthesis of a triazole-based inhibitor of Met functions in cancer cells.
January 1st, 2012
Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling.
August 15th, 2011
MET signaling in GABAergic neuronal precursors of the medial ganglionic eminence restricts GDNF activity in cells that express GFRα1 and a new transmembrane receptor partner.
August 2nd, 2011
Genetic analysis of specific and redundant roles for p38alpha and p38beta MAPKs during mouse development.
June 1st, 2011
Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo.
March 1st, 2011
Fine-tuning of cell signaling by glypicans.
April 1st, 2010
Somitic origin of the medial border of the mammalian scapula and its homology to the avian scapula blade.
October 17th, 2008
A new Met inhibitory-scaffold identified by a focused forward chemical biological screen.
May 22nd, 2007
Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis.
January 5th, 2007
Glypicans are differentially expressed during patterning and neurogenesis of early mouse brain.
June 15th, 2006
Imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action mechanism.
February 24th, 2006
Combined signaling through ERK, PI3K/AKT, and RAC1/p38 is required for met-triggered cortical neuron migration.
October 24th, 2005
Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.
March 15th, 2005
Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies.
February 1st, 2005
A dual fate of the hindlimb muscle mass: cloacal/perineal musculature develops from leg muscle cells.
December 1st, 2004
Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage.
August 28th, 2003
Met signaling is required for recruitment of motor neurons to PEA3-positive motor pools.
June 1st, 2001