CONTACT

Fabrice Lavial
fabrice.lavial@lyon.unicancer.fr
phone : 04 69 16 66 13
Cheney A - second floor


LAVIAL Fabrice
HUYGHE Aurélia
FURLAN Giacomo
WAJDA Pauline
COMBEMOREL Noémie
RUEL Maeva

Research engineer
maeva.ruel@univ-lyon1.fr

Voir les objectifs et projets Voir les publications
Collaborations

 Jesus Gil - Imperial college london, UK
Alexander Meissner, Max Planck institute, Germany
Jose Polo, Monash university, Australia

Fundings
Equipe labellisée 'La Ligue contre le cancer'
Labex DEV2CAN
Atip-avenir
Association, pour la recherche contre le cancer
Fondation pour la recherche médicale
INCa

OBJECTIVES

Cellular plasticity and dedifferentiation are key features of cellular reprogramming and oncogenesis. Embryo lineage segregation leads to a restriction of such plasticity upon differentiation. In contrast, this property is regained when the epigenome of a somatic cell is dedifferentiated and reprogrammed toward the pluripotent state to generate iPS cells (induced pluripotent cells). The oncogenic reprogramming process also frequently involves the reacquisition of developmental programs.
 
The team is developing large-scale approaches and original genetic models to decipher the molecular events triggering pluripotent and oncogenic reprogramming (Axis#1)(Ozmadenci D. et al., Nature Communications 2015)(Puisieux A. et al, Cancer Cell 2018). In parallel, we are exploring the molecular mechanisms that control pluripotent stem cell self-renewal (embryonic or induced) with a particular focus on the netrin-1 signaling pathway (Huyghe A. et al., Nature Cell Biology, accepted 2019). The main objective is the identification of novel factors/mechanisms governing cellular identity in order to (i) improve pluripotent stem cells generation and maintenance for regenerative medicine and (ii) broaden our understanding of the oncogenic development.
 

PROJECT

Axis#1: Deciphering the reprogramming roadmaps toward pluripotency and malignancy

Dedifferentiation and cellular plasticity are key features of pluripotent and oncogenic reprogramming (Figure 1). Such plasticity is regained when the epigenome of a somatic cell is induced to dedifferentiate and reprogrammed toward the pluripotent state by the transcription factors Oct4, Sox2, Klf4 and c-Myc (iPS cells - induced pluripotent cells). The iPS cells generation process opened new avenues for regenerative medicine but the approaches are still limited by the poor efficiency of the procedure and by the wide differentation potential of the resulting iPS cells. Understanding the molecular mechanisms triggering the early steps of PR is crucial for the efficient generation of high-quality iPS cells.

Plasticity features are also re-acquired at multiple stages of oncogenesis, with the example of oncogenic reprogramming induced by mutated Ras and c-Myc that involves dedifferentiation and reacquisition of developmental programs. However, even if oncogenic reprogramming and dedifferentiation are considered as fundamental steps in cancer initiation, the molecular networks precluding the conversion of a somatic cell to a tumorigenic state remain unclear. The development of models recapitulating the early steps of oncogenic reprogramming is crucial to broaden our understanding of cancer initiation.

 The main objective of the team is to identify novel factors/mechanisms governing dedifferentiation. We are particularly deciphering the initial steps triggering the reprogramming of a somatic cell toward the pluripotent and/or oncogenic states. To do so, we developed in the past years large-scale approaches and original genetic models to tackle such biological questions. Our efforts recently led to the identification of the Netrin-1 signalling pathway as a novel reprogramming roadblock (Lavial F. et al., patent 2014 and Ozmadenci D. et al., Nature Communications 2015) and the Bcl11a and Bcl11b transcription factors as regulators of cell identity (Huyghe A. et al., submitted).

Axis#2: Control of pluripotent stem cell self-renewal

A better understanding of stem cell self-renewal is a crucial objective for regenerative medicine and cancer biology. We are using rodent and human pluripotent stem cells (embryonic or induced) in the lab to identify crucial regulators of the undifferentiated state. Our recent work led to the identification of the netrin-1 ligand and its receptors Unc5b and Neo1 as crucial regulators of naive pluripotency (Huyghe A. et al., Nature Cell Biology 2019). We are now exploring the associated molecular cascade in normal and pathological stem cells.

 

PUBLICATIONS

2019
-Huyghe A., Furlan G., Ozmadenci D., Galonska C., Charlton J., Gaume X., Combémorel N., Riemenschneider C., Allègre N., Zhang J., Wajda P., Rama N., Vieugué P., Durand I., Brevet M., Gadot N., Imhof T., Merrill B., Koch M., Mehlen P., Chazaud C., Meissner A. and Lavial F
Netrin-1 promotes naïve pluripotency through Neo1 and Unc5b co-regulation of Wnt and Mapk signalling.
Nature Cell Biology, accepted

2018
-Puisieux A., Pommier R., Morel A.P. and Lavial F.
Cellular Pliancy and the Multistep Process of Tumorigenesis. review. 
Cancer Cell

2016
-Mehlen P. and Lavial F.
The netrin-1 cue regulates somatic cell reprogramming to pluripotency. 
Médecine sciences

2015
-Ozmadenci D., Feraud O., Markossian S., Kress E., Ducarouge B., Gibert B., Jeng G., Durand I., Gadot N., Scoazec JY., Bennaceur-Griscelli A., Plateroti M., Gil J., Deng H., Bernet A., Mehlen P and Lavial F.
Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance. 
Nature Communications

Granted patents:
-Lavial F., Bernet A., Mehlen P.
Use of recombinant Netrin-1 protein treatment to improve the generation of mouse and human induced pluripotent stem cells.
Patent n°1450252 (2014).

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