Signalling networks for stemness and tumorigenesis

Publications / Peer-reviewed journal

Y. Fan, M. Arechederra, S. Richelme, F. Daian, C. Novello, J. Caldero, L. Di Tommaso, G. Morcrette, S. Rebouissou, M. Donadon, E. Morenghi, J. Zucman-Rossi, M. Roncalli, R. Dono, F. Maina. A Phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of non-oncogenic RTKs. Hepatology, 66(5):1644-1661 (2017).
Our genetic studies highlight the heightened vulnerability of liver cells to subtle changes in non-oncogenic RTK levels, allowing them to acquire a molecular profile that facilitates the full tumorigenic program. Furthermore, outcomes uncover new synthetic lethal interactions as potential therapies for a cluster of HCC patients.

This paper has been acknowledged on the CNRS web site:

F. Lamballe, S. Toscano, F. Conti, M. Arechederra, N. Baeza, D. Figarella-Branger, F. Helmbacher, F. Maina. Coordination of signalling networks and cell tumorigenic properties by Abl in glioblastoma cells. Oncotarget, 7(46):74747-74767 (2016).
We showed that GBM cells are highly vulnerable to Abl inhibition as evidenced by loss of tumorigenic and self-renewal properties accompanied by drastic changes in the expression and/or phosphorylation levels of multiple signalling components. Such molecular and biological state is reverted when Abl signalling is restored, demonstrating the reversibility of changes in cell competence.

Y. Fan, S. Richelme, E. Avazeri, S. Audebert, F. Helmbacher, R. Dono, F. Maina. Tissue-specific gain of RTK signalling uncovers selective cell vulnerability during embryogenesis. PLoS Genetics, Sep 22;11(9):e1005533 (2015).
Our findings show that the accomplishment of developmental programs is ensured by the robustness of cell competence to buffer increased fluctuations of RTKs and to integrate them into functional circuits. Findings also illustrate that developmental programs are rather sensitive to alterations in tissue-spatial distribution of RTK action.

A. Hultberg, V. Morello, L. Huyghe, N. De Jonge, C. Blanchetot, V. Hansses, G. de Boeck, K. Silence, E. Festjens, R. Heukers, B. Roux, F. Lamballe, C. Ginestier, E. Charafe-Jauffret, F. Maina, P. Brouckaert, M. Saunders, A. Thibault, T. Dreier, H. de Haard, P. Michieli. Killing MET-expressing tumor cells by ADCC provides a therapeutic advantage over inhibiting HGF/MET signaling. Cancer Research, 75(16):3373-83 (2015).

Caruso N., Herberth B., Lamballe F., Arce-Gorvel V., Maina F.*, and Helmbacher F.* Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons. BMC Biology, 12(1):56 (2014).
Our findings show that in motor neurons, alternative Met signalling cascades are equivalent to ensure cell survival, but not interchangeable for axon guidance and cell fate specification; thus, the degree of equivalence of signalling cascades by RTK depends on the type of biological outcomes within a developmental program and it is refined by the type of cells.

A.  Fico, A. de Chevigny, C. Melon, M. Bohic, L. Kerkerian-Le Goff, F. Maina, R. Dono*, and H. Cremer*. Reducing Glypican-4 in ES cells improves recovery in a rat model of Parkinson's disease by increasing the production of dopaminergic neuron and decreasing teratoma formation. J. Neuroscience 34(24):8318-23 (2014).
Our findings show that Glypican4 modulation leads mouse ESCs to an “uncoupled state” that permits enhanced differentiation in dopaminergic neurons and motor functional recovery when transplanted into Parkinsonian rats without teratomas.

F. Maina. Strategies to overcome drug resistance of receptor tyrosine kinase-addicted cancer cells. Current Medicinal Chemistry 21(14):1607-17 (2014).
By revisiting mechanisms of drug resistance found in cancer cells and by intercalating new emerging concepts on RTK signaling coming from cancer genome studies, this review discusses strategies aimed to enhance the effectiveness of RTK blocking agents and overcome resistance to treatment.

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. and Helmbacher F. Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of Facioscapulohumeral dystrophy. PLoS Genet 9(6): e1003550 (2013). doi:10.1371/journal.pgen.1003550.

M. Arechederra, R. Carmona, M. González-Nuñez, Á. Gutiérrez-Uzquiza, P. Bragado, I. Cruz-González, E. Cano, C. Guerrero, A. Sánchez, J.M. López-Novoa, M.D. Schneider, F. Maina, R. Muñoz-Chápuli, and A. Porras. Met signaling in cardiomyocytes is required for normal cardiac function in adult mice. BBA - Molecular Basis of Disease 1832(12):2204-15 (2013).

A. Furlan, F. Conti, N. Issaly, B. Roux, F. Lamballe, S. Richelme, J. Bosch, D. Passarella, O. Piccolo, R. Dono and F. Maina. Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells with oncogenic Met signaling. PLoS ONE 7(10): e46738. doi:10.1371/journal.pone.0046738
Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels.

A. Furlan, F. Lamballe, V. Stagni, A. Hussain, S. Richelme, A. Prodosmo, A. Moumen, C. Brun, I. del Barco Barrantes, J. S. C. Arthur, A. J. Koleske, A. R. Nebreda, D. Barilà and F. Maina. Met acts through Abl to regulate p53 transcriptional outcomes and cell survival in the developing liver. J. of Hepatology, 10.1016/j.jhep.2012.07.044.
Our findings demonstrate that the robustness of core pathways in oncogenesis comes also into play during embryogenesis and raise the provocative idea that RTKs such as Met can instruct p53 to participate to developmental and oncogenic programs, by qualitatively tuning its transcriptional properties. 

A. Fico, A. De Chevigny, J. Egea, M. Bôsl, H. Cremer, F. Maina and R. Dono. Modulating glypican4 suppresses tumorigenicity of embryonic stem cells while preserving self-renewal and pluripotency
. Stem Cells, 2012 Jul 3. doi: 10.1002/stem.1165. [Epub ahead of print].
Our findings establish that Glypican4 acts at the interface of extrinsic and intrinsic signal regulation to fine tune stem cell fate and show the possibility to uncouple pluripotent stem cell differentiation from tumorigenic potential by acting on Glypican4.

Francesco Colombo, Cristina Tintori, Alessandro Furlan, Stella Borrelli, Michael S. Christodoulou, Rosanna Dono, Flavio Maina, Maurizio Botta, Mercedes Amat, Joan Bosch, Daniele Passarella. ‘Click’ synthesis of a triazole-based inhibitor of Met functions in cancer cells. Bioorganic & Medicinal Chemistry Letters (2012), doi:

A. Furlan, F. Colombo, A. Kover, N. Issaly, C. Tintori, L. Angeli, S. Letard, V. Leroux, M. Amat, B. Maigret, P. Dubreuil, M. Botta, R. Dono, J. Bosch, O. Piccolo, D. Passarella and F. Maina. Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitor of tumorigenesis by oncogenic Met signaling. European Journal of Medicinal Chemistry, 47(1):239-54 (2012).

F. Lamballe, M. Genestine, N. Caruso, V. Arce, S. Richelme, F. Helmbacher* and F. Maina*. Pool-specific regulation of motor neuron survival by neurotrophic support. J. Neuroscience 31(31):11144-58 (2011).
Our findings demonstrate the exquisite degree to which outcomes of signaling by RTKs are regulated on a cell-by-cell basis.

I. del Barco Barrantes, J.M. Coya, F. Maina, J.S.C. Arthur and A.R. Nebreda. Genetic analysis of specific and redundant roles for p38? and p38? MAPKs during mouse development. PNAS 108(31):12764-9 (2011).

M. Perrinjaquet, D. Sjöstrand, A. Moliner, S. Zechel, F. Lamballe, F. Maina and C. F. Ibáñez. Met signaling in GABAergic neurons of the medial ganglionic eminence restricts GDNF activities in cells expressing GFRalpha1 and a novel transmembrane receptor. J. of Cell Science 124(Pt 16):2797-805 (2011).

A. Furlan, V. Stagni, A. Hussain, S. Richelme, F. Conti, A. Prodosmo, A. Destro, M. Roncalli, D. Barilà* and F. Maina*. Abl interconnects oncogenic Met and p53 core pathways in cancer cells. Cell Death & Differentiation doi:10.1038/cdd.2011.23 (2011).
Our findings introduce the concept that tumorigenesis driven by oncogenic RTKs can be therapeutically targeted by hitting vulnerable signals, although not mutated, that function as signaling nodes interconnecting core pathways.
M. Genestine, E. Caricati, A. Fico, S. Richelme, H. Hassani, C. Sunyach, F. Lamballe, G.C. Panzica, B. Pettmann, F. Helmbacher, C. Raoul, F. Maina* and R. Dono*. Enhanced neuronal Met signalling levels in ALS mice delay disease onset. Cell Death & Disease 17;2:e130 (2011).
Our findings highlight the properties of RTKs to counteract toxic signals in a disease characterized by dysfunction of multiple cell types by acting in motor neurons and emphasize the relevance of genetically assessing the effectiveness of agents targeting neurons during ALS evolution. 

L. Tönges, T. Ostendorf, F. Lamballe, M. Genestine, R. Dono, J.C. Koch, M. Bähr, F. Maina* and P. Lingor*. Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo. J. Neurochemistry 117(5): 892-903 (2011).

E. Gascon, S. Gaillard, P. Malapert, Y. Liu, F. Helmbacher, F. Maina and A. Moqrich. Hepatocyte Growth Factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons. J. Neuroscience 30(37):12414 –12423 (2010).

E. Krejci, M. Grim, F. Maina, Y. Shwartz, A. Otto, R. Huang and K. Patel. Somitic origin of the medial border of the mammalian scapula and its homology to the avian scapula blade. J. of Anatomy 216(4):482-8 (2010).

Y. Asses, V. Leroux, S. Tairi-Kellou, R. Dono, F. Maina and B. Maigret. Analysis of c-Met kinase domain complexes: a new specific catalytic site receptor model for defining binding modes of ATP-competitive ligands. Chemical Biology & Drug Design. 74(6): 560-570 (2009).
S. Patané, N. Pietrancosta, H. Hassani, V. Leroux, B. Maigret, J.L. Kraus, R. Dono and F. Maina. A new Met inhibitory-scaffold identified by a focused forward chemical biological screen. Biochem. Biophys. Res. Commun. 375:184-9 (2008).

A. Moumen, S. Patané, A. Porras, R. Dono and F. Maina. mTOR acts through Mdm2 to signal cell survival in vivo. Development 134:1443-51 (2007).
A. Moumen, A. Ieraci, S. Patané, C. Solé, J. Comella, R.Dono and F. Maina. Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3K/Akt dependent manner. Hepatology 45: 1210-7 (2007).

P. Fazzari, J. Penachioni, S. Gianola, F. Rossi, B.J. Eickholt, F. Maina, L. Alexopoulou, A. Sottile, P.M. Comoglio, R.A. Flavell and L. Tamagnone. Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis. BMC Dev Biol. 7:55-67 (2007).

G. Luxardi, A.Galli, S. Forlani, K. Lawson, F. Maina and R. Dono. Glypicans are differentially expressed during patterning and neurogenesis of early mouse brain. Biochem. Biophys. Res. Commun. 352: 55-60 (2007).

N. Pietrancosta, A. Moumen, R. Dono, P. Lingor, V. Planchamp, F. Lamballe, M. Bähr, J.L. Kraus* and F. Maina*. Imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action mechanism. J. Med. Chem. 49: 3645-52 (2006).
J. Segarra, L. Balenci, T. Drenth, F. Maina* and F. Lamballe*. Combined signaling through ERKs, PI3K/Akt and Rac1/p38 is required for Met-triggered cortical neuron migration. J. Biol. Chem. 281: 4771-8 (2006). This article was selected as a Paper of the Week.
G. Pante, J. Thompson, F. Lamballe, T. Iwata, F.A. Barr, A.M. Davies, F. Maina and R. Klein. Mitogen-inducible-gene-6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth. J. Cell Biol. 171: 337-48 (2005).
N. Pietrancosta, F. Maina, R. Dono, A. Moumen, C. Garino, S. Burlet, G. Quéléver and J.L. Kraus. Novel cyclised Pifithrin-a p53 inactivators: synthesis and biological studies. Bioorganic and molecular chemistry letters 15: 1561-4 (2005).
P. Valasek, D.J.R. Evans, F. Maina, M. Grim and K. Patel. A dual fate of the hindlimb muscle mass: cloacal/perineal musculature develops from leg muscle cells. Development 132: 447-58 (2005).
D. Tulasne, J. Deheuninck, F.C. Lourenço, F. Lamballe, Z. Ji, C. Leroy, E. Puchois, A. Moumen, F. Maina, P. Mehlen and V. Fafeur. Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage. Molecular and Cellular Biology 24(23): 10328-39 (2004).
F. Helmbacher, E. Dessaud, S. Arber, O. deLapeyrière, C. Henderson, R. Klein and F. Maina. Met signaling is required for recruitment of motor neurons to Pea3-positive motor pools. Neuron 39, 767-77 (2003).
F. Maina, G. Pante’, F. Helmbacher, A. Renvaktar, R. Andres, A.M. Davies, C. Ponzetto, and R. Klein. Coupling Met to specific pathways results in distinct developmental outcomes. Molecular Cell 7, 1293-306 (2001).

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last updated 13/10/2017