CONTACT

Fabrice Lavial

Principal investigator
ATIP/Avenir

fabrice.lavial@lyon.unicancer.fr

phone : 04 69 16 66 13

Cheney A - first floor
Centre Léon Bérard

LAVIAL Fabrice

Chef d'équipe, CR1 Inserm 

fabrice.lavial@lyon.unicancer.fr
HUYGHE Aurélia
OZMADENCI Duygu

Etudiante en thèse (duygu.ozmadenci@lyon.unicancer.fr)

FURLAN Giacomo
WAJDA Pauline

Ingénieur d'étude (pauline.wajda@lyon.unicancer.fr)

VENET Manon

Etudiante en M1

Voir les objectifs et projets Voir les publications
Collaborations

 Jesus Gil - Imperial college london, UK
Veronique Azuara
 - Imperial college london, UK

Hongkui Deng - Peking university, China


Mathieu Gabut - Centre de recherche en Cancérologie de Lyon, France


Ian Chambers - University of Edinburgh, UK

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. The main objective is the identification of novel factors/mechanisms governing dedifferentiation in order to (i) improve iPS cells generation process for regenerative medicine and (ii) broaden our understanding of the oncogenic development.
 

PROJECT

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).

PUBLICATIONS

2015
1-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.
* Co-senior author. Nature Communications. (PMID 26154507)

2014
2-Gibert B., Delloye-Bourgeois C., Gattolliat CH., Meurette O., Le Guernevel S., Fombonne J., Ducarouge B., Lavial F., Bouhallier F., Creveaux M., Negulescu AM., Bénard J., Janoueix-Lerosey I., Harel-Bellan A., Delattre O., Mehlen P. Regulation by miR181 Family of the Dependence Receptor CDON Tumor Suppressive Activity in Neuroblastoma.
J. Natl. Cancer. Inst. (PMID: 25313246)

2013
3-Genevois AL., Ichim G., Coissieux MM., Lambert MP., Lavial F., Goldschneider D., Jarrosson-Wuilleme L., Lepinasse F., Gouysse G., Herceg Z., Scoazec JY., Tauszig-Delamasure S., Mehlen P. Dependence receptor TrkC is a putative colon cancer tumor suppressor.
Proc Natl Acad Sci U S A. (PMID: 23341610)

2012
4-Lavial F., Bessonnard S., Ohnishi Y., Tsumura A., Chandrashekran A., Fenwick MA., Tomaz RA., Hosokawa H., Nakayama T., Chambers I., Hiiragi T., Chazaud C., Azuara V. Bmi1 facilitates primitive endoderm formation by stabilizing Gata6 during early mouse development.
Genes & Development. (PMID: 22713603)

5-Percharde M., Lavial F., Ng J., Kumar V., Prabhakar S., Gil J., Ng H., Parker M., Azuara V. Ncoa3 functions as essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogramming. 
Genes & Development. (PMID: 23019124)

6-O'Loghlen A., Muñoz-Cabello AM., Gaspar-Maia A., Wu HA., Banito A., Kunowska N., Racek T., Pemberton HN., Beolchi P., Lavial F., Masui O., Vermeulen M., Carroll T., Graumann J., Heard E., Dillon N., Azuara V., Snijders AP., Peters G., Bernstein E., Gil J. MicroRNA regulation of Cbx7 mediates a switch of Polycomb orthologs during ESC differentiation.
Cell Stem Cell. (PMID: 22226354)

7-Acloque H., Lavial F., Pain B. Astacin-like metallo-endopeptidase is dynamically expressed in embryonic stem cells and embryonic epithelium during morphogenesis.
Developmental Dynamics. (PMID: 22275110)

2011
8-Theunissen TW., Costa Y., Radzisheuskaya A., van Oosten AL., Lavial F., Pain B., Castro LF., Silva JC. Reprogramming capacity of Nanog is functionally conserved in vertebrates and resides in a unique homeodomain.
Development. (PMID: 22028025)

2010
8-Lavial F*., Alder O*., Helness A., Brookes E., Pinho S., Chandrashekran A., Arnaud P., Pombo A., O’Neill L., Azuara V. Ring1B and Suv39h1 delineate distinct chromatin states at bivalent genes during early mouse lineage commitment. *co-first author.
Development. (PMID: 20573702)

9-Bouhallier F., Allioli N., Lavial F., Chalmel F., Perrard MH., Durand P., Samarut J., Pain B., Rouault JP. Role of miR34c microRNA in the late steps of spermatogenesis.
RNA. (PMID: 20150330)

2009
10-Lavial F., Acloque H., Bachelard E. , Nieto A., Samarut J., Pain B. The RNA binding protein Chicken Vasa Homologue is sufficient to program embryonic stem cells to the germ fate.
Developmental Biology. (PMID: 19324033)

2007
11-Lavial F., Acloque H., Bertocchini F., MacLeod D.J., Boast, S., Bachelard E., Montillet G., Thenot S., Sang H.M., Stern C.D., Samarut J., Pain B. Chicken PouV, a homologue of Oct4, and Nanog regulate pluripotency in chicken embryonic stem cells.
Development. (PMID: 17827181)
 

Granted patents:
 
1-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).
 
2-Pain B., Bouhaillier F., Lavial F., Rouault JP., Samarut J. Method for reprogramming in vitro stem cells and somatic cells into germinal cells. PCT/EP2008/067353 (2008).
 
3-Pain B., Lavial F., Bachelard E., Montillet G, Samarut J. Combination of markers delineating avian pluripotent cells. Patent N° FR 06/02592 and PCT (2006).
 
4-Pain B., Lavial F., Samarut J. Preparation of avian differentiated cells and genes involved in pluripotency. Patent N° FR 06/02597 and PCT (2006).

Review articles:
 
1-Jean C., Aubel P., Soleihavoup C., Bouhallier F., Voisin S., Lavial F., Pain B. Pluripotent genes in avian stem cells.
Development growth and Differentiation (2013). (PMID: 23278808)

2-Lavial F., Pain B. Chicken embryonic stem cells as a non-mammalian embryonic stem cell model.
Development Growth and Differentiation (2010). (PMID: 20039925)

3-Lavial F., Acloque H., Bachelard E., Montillet G., Nieto A., Samarut J., Pain B. Molecular control of  pluripotency and germline competency in chick ES cells.
Cell research (2008).

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