TEAM

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.

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.
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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, 13-4.9, neurons from ES
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.


Main publications

PUBLICATION

A Phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of non-oncogenic RTKs

Fan Y, Arechederra M, Richelme S, Daian F, Novello C, Calderaro J, Di Tommaso L, Morcrette G, Rebouissou S, Donadon M, Morenghi E, Zucman-Rossi J, Roncalli M, Dono R, Maina F.
Hepatology. 2017 Jun 6. PMID: 28586114

PUBLICATION

Coordination of signalling networks and tumorigenic properties by ABL in glioblastoma cells

Fabienne Lamballe, Sara Toscano, Filippo Conti, Maria Arechederra, Nathalie Baeza, Dominique Figarella-Branger, Françoise Helmbacher and Flavio Maina
Oncotarget. 2016 Oct 9. PMID: 27732969

PUBLICATION

Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis.

Fan Y, Richelme S, Avazeri E, Audebert S, Helmbacher F, Dono R, Maina F.
PLoS Genet. 2015 Sep 22;11(9):e1005533. doi: 10.1371/journal.pgen.1005533. eCollection 2015. PMID: 26393505

PUBLICATION

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.

Fico A, de Chevigny A, Melon C, Bohic M, Kerkerian-Le Goff L, Maina F, Dono R, Cremer H.
J Neurosci. 2014 Jun 11;34(24):8318-23. PMID: 24920634

PUBLICATION

Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy.

Caruso N, Herberth B, Bartoli M, Puppo F, Dumonceaux J, Zimmermann A, Denadai S, Lebossé M, Roche S, Geng L, Magdinier F, Attarian S, Bernard R, Maina F, Levy N, Helmbacher F.
PLoS Genet. 2013 Jun;9(6):e1003550. PMID: 23785297

PUBLICATION

Met acts through Abl to regulate p53 transcriptional outcomes and cell survival in the developing liver.

Furlan A, Lamballe F, Stagni V, Hussain A, Richelme S, Prodosmo A, Moumen A, Brun C, Del Barco Barrantes I, Arthur JS, Koleske AJ, Nebreda AR, Barilà D, Maina F.
J Hepatol. 2012 Dec;57(6):1292-8. PMID: 22889954

PUBLICATION

Modulating Glypican4 suppresses tumorigenicity of embryonic stem cells while preserving self-renewal and pluripotency.

Fico A, De Chevigny A, Egea J, Bösl MR, Cremer H, Maina F, Dono R.
Stem Cells. 2012 Sep;30(9):1863-74. PMID: 22761013

PUBLICATION

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures.

Furlan A, Roux B, Lamballe F, Conti F, Issaly N, Daian F, Guillemot JF, Richelme S, Contensin M, Bosch J, Passarella D, Piccolo O, Dono R, Maina F.
PLoS One. 2012;7(10):e46738. PMID: 23071625

PUBLICATION

Abl interconnects oncogenic Met and p53 core pathways in cancer cells.

Furlan A, Stagni V, Hussain A, Richelme S, Conti F, Prodosmo A, Destro A, Roncalli M, Barilà D, Maina F.
Cell Death Differ. 2011 Oct;18(10):1608-16. PMID: 21455220

PUBLICATION

Pool-specific regulation of motor neuron survival by neurotrophic support.

Lamballe F, Genestine M, Caruso N, Arce V, Richelme S, Helmbacher F*, Maina F*. (* co-senior authors)
J Neurosci. 2011 Aug 3;31(31):11144-58. PMID: 21813676

PUBLICATION

Enhanced neuronal Met signalling levels in ALS mice delay disease onset.

Genestine M, Caricati E, Fico A, Richelme S, Hassani H, Sunyach C, Lamballe F, Panzica GC, Pettmann B, Helmbacher F, Raoul C, Maina F, Dono R.
Cell Death Dis. 2011 Mar 17;2:e130. PMID: 21412276

PUBLICATION

Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons.

Gascon E, Gaillard S, Malapert P, Liu Y, Rodat-Despoix L, Samokhvalov IM, Delmas P, Helmbacher F, Maina F, Moqrich A.
J Neurosci. 2010 Sep 15;30(37):12414-23. PMID: 20844136

PUBLICATION

Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner.

Moumen A, Ieraci A, Patané S, Solé C, Comella JX, Dono R, Maina F.
Hepatology. 2007 May;45(5):1210-7. PMID: 17464994

PUBLICATION

Met acts on Mdm2 via mTOR to signal cell survival during development.

Moumen A, Patané S, Porras A, Dono R, Maina F.
Development. 2007 Apr;134(7):1443-51. PMID: 17329361
Other publications

PUBLICATION

Met signaling in cardiomyocytes is required for normal cardiac function in adult mice.

Arechederra M, Carmona R, González-Nuñez M, Gutiérrez-Uzquiza A, Bragado P, Cruz-González I, Cano E, Guerrero C, Sánchez A, López-Novoa JM, Schneider MD, Maina F, Muñoz-Chápuli R, Porras A.
Biochim Biophys Acta. 2013 Aug 28. PMID: 23994610

PUBLICATION

Strategies to Overcome Drug Resistance of Receptor Tyrosine Kinase-Addicted Cancer Cells.

Maina F.
Curr Med Chem. 2013 Aug 23. PMID: 23992334

PUBLICATION

Analysis of c-Met kinase domain complexes: a new specific catalytic site receptor model for defining binding modes of ATP-competitive ligands.

Asses Y, Leroux V, Tairi-Kellou S, Dono R, Maina F, Maigret B.
PMID: 19909299

PUBLICATION

'Click' synthesis of a triazole-based inhibitor of Met functions in cancer cells.

Colombo F, Tintori C, Furlan A, Borrelli S, Christodoulou MS, Dono R, Maina F, Botta M, Amat M, Bosch J, Passarella D.
Bioorg Med Chem Lett. 2012 Jul 15;22(14):4693-6. PMID: 22738633

PUBLICATION

Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling.

Furlan A, Colombo F, Kover A, Issaly N, Tintori C, Angeli L, Leroux V, Letard S, Amat M, Asses Y, Maigret B, Dubreuil P, Botta M, Dono R, Bosch J, Piccolo O, Passarella D, Maina F.
Eur J Med Chem. 2012 Jan;47(1):239-54. PMID: 22138308

PUBLICATION

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.

Perrinjaquet M, Sjöstrand D, Moliner A, Zechel S, Lamballe F, Maina F, Ibáñez CF.
J Cell Sci. 2011 Aug 15;124(Pt 16):2797-805. PMID: 21807944

PUBLICATION

Genetic analysis of specific and redundant roles for p38alpha and p38beta MAPKs during mouse development.

del Barco Barrantes I, Coya JM, Maina F, Arthur JS, Nebreda AR.
Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12764-9. PMID: 21768366

PUBLICATION

Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo.

Tönges L, Ostendorf T, Lamballe F, Genestine M, Dono R, Koch JC, Bähr M, Maina F, Lingor P.
J Neurochem. 2011 Jun;117(5):892-903. PMID: 21443522

PUBLICATION

Fine-tuning of cell signaling by glypicans.

Fico A, Maina F, Dono R.
Cell Mol Life Sci. 2011 Mar;68(6):923-9. PMID: 18087675

PUBLICATION

Somitic origin of the medial border of the mammalian scapula and its homology to the avian scapula blade.

Valasek P, Theis S, Krejci E, Grim M, Maina F, Shwartz Y, Otto A, Huang R, Patel K.
J Anat. 2010 Apr;216(4):482-8. PMID: 20136669

PUBLICATION

A new Met inhibitory-scaffold identified by a focused forward chemical biological screen.

Patané S, Pietrancosta N, Hassani H, Leroux V, Maigret B, Kraus JL, Dono R, Maina F.
Biochem Biophys Res Commun. 2008 Oct 17;375(2):184-9. PMID: 18703015

PUBLICATION

Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis.

Fazzari P, Penachioni J, Gianola S, Rossi F, Eickholt BJ, Maina F, Alexopoulou L, Sottile A, Comoglio PM, Flavell RA, Tamagnone L.
BMC Dev Biol. 2007 May 22;7:55. PMID: 17519029

PUBLICATION

Glypicans are differentially expressed during patterning and neurogenesis of early mouse brain.

Luxardi G, Galli A, Forlani S, Lawson K, Maina F, Dono R.
Biochem Biophys Res Commun. 2007 Jan 5;352(1):55-60. PMID: 17107664

PUBLICATION

Imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action mechanism.

Pietrancosta N, Moumen A, Dono R, Lingor P, Planchamp V, Lamballe F, Bähr M, Kraus JL, Maina F.
J Med Chem. 2006 Jun 15;49(12):3645-52. PMID: 16759106

PUBLICATION

Combined signaling through ERK, PI3K/AKT, and RAC1/p38 is required for met-triggered cortical neuron migration.

Segarra J, Balenci L, Drenth T, Maina F, Lamballe F.
J Biol Chem. 2006 Feb 24;281(8):4771-8. PMID: 16361255

PUBLICATION

Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.

Pante G, Thompson J, Lamballe F, Iwata T, Ferby I, Barr FA, Davies AM, Maina F, Klein R.
J Cell Biol. 2005 Oct 24;171(2):337-48. PMID: 16247031

PUBLICATION

Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies.

Pietrancosta N, Maina F, Dono R, Moumen A, Garino C, Laras Y, Burlet S, Quéléver G, Kraus JL.
Bioorg Med Chem Lett. 2005 Mar 15;15(6):1561-4. PMID: 15745797

PUBLICATION

A dual fate of the hindlimb muscle mass: cloacal/perineal musculature develops from leg muscle cells.

Valasek P, Evans DJ, Maina F, Grim M, Patel K.
Development. 2005 Feb;132(3):447-58. PMID: 15653949

PUBLICATION

Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage.

Tulasne D, Deheuninck J, Lourenco FC, Lamballe F, Ji Z, Leroy C, Puchois E, Moumen A, Maina F, Mehlen P, Fafeur V.
Mol Cell Biol. 2004 Dec;24(23):10328-39. PMID: 15542841

PUBLICATION

Met signaling is required for recruitment of motor neurons to PEA3-positive motor pools.

Helmbacher F, Dessaud E, Arber S, deLapeyrière O, Henderson CE, Klein R, Maina F.  
Neuron. 2003 Aug 28;39(5):767-77. PMID: 12948444

PUBLICATION

Coupling Met to specific pathways results in distinct developmental outcomes.

Maina F, Panté G, Helmbacher F, Andres R, Porthin A, Davies AM, Ponzetto C, Klein R.
Mol Cell. 2001 Jun;7(6):1293-306. PMID: 11430831

Members more

Fahmida Ahmad     Serena Corti Rosanna Dono Fabienne Lamballe Diane Rattier Sylvie Richelme
Flavio Maina
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Flavio Maina

Researcher

Fahmida Ahmad
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Fahmida Ahmad

PhD student

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Sehrish khan Bazai

PhD student

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Remi Bonjean

Technical staff

Serena Corti
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Serena Corti

PhD student

Rosanna Dono
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Rosanna Dono

Researcher

Rosanna (DR2 Inserm) joined the group in 2004, bringing a strong background in developmental biology and mouse genetics. Rosanna is interested on the functional analysis of signalling networks in stem cell fate regulation and she aims at translating acquired knowledge into new therapies for central nervous system repair. She is leading the project 'Signalling network crosstalk uncoupling tumorigenicity from therapeutic properties of human iPSCs'.

Fabienne Lamballe
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Fabienne Lamballe

Researcher

Diane Rattier
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Diane Rattier

PhD student

Sylvie Richelme
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Sylvie Richelme

Technical staff