Normal and Pathological Development of Melanocytes

Larue

Lionel Larue Team Leader Tel:

Skin cancers and especially melanomas are constantly increasing in western countries with their incidence doubling every 12 years. Epidemiological reasons are quite clear: sun, pollution, ethnical migration and lifestyle.

 

Figure 1: Représentation schématique de l’initiation et de la progression de mélanome cutané; un processus multi-étapes. La mélanomagenèse utilise différents mécanismes cellulaires qui sont associés à des mutations activatrices / induction de l’expression d’oncogène (en rouge - NRAS, BRAF ou/et β-caténine), ou des mutations inactivatrices / répression de l’expression de suppresseur de tumeurs (en bleu - NF1, p16, PTEN ou/et CDH1). RGP, phase radiale de croissance ; VGP, phase verticale de croissance (voir Conde-Perez et Larue, 2014).
Schematic representation of melanoma initiation and progression as a multistep process. Melanomagenesis involves various cellular mechanisms which are associated with oncogene expression / activation (in red NRAS, BRAF or/and β-catenin) or inactivation / downregulation of tumor suppressor (in blue, NF1, p16, PTEN or/and CDH1) proteins. RGP, radial growth phase; VGP, vertical growth phase; (see Conde-Perez and Larue, 2014)

However, the molecular mechanisms associated with this transformation are not yet fully elucidated, even though proteins belonging to the MAP-kinase, PI3K and β-catenin pathways were clearly shown to be involved. In order to better understand melanomagenesis, cellular heterogeneity and plasticity, and melanoma resistance we investigate the establishment and the renewal of the melanocyte lineage, as well as melanomagenesis.

 

It is becoming very clear that the MAP-kinase pathway induces melanocyte proliferation and senescence. Similarly, the lack of PTEN or p16, or the activation of b-catenin allows the bypass of senescence. However, the vast majority of the cells which are mutated for two of these types of proteins are not able to initiate a melanoma. This indicates that melanoma initiation is still not fully understood. Melanoma initiation is followed by progression (involving most probably CDH1) and associated molecular heterogeneity (involving most probably MITF and BRN2).

 

Figure 2 : La coopération des mutations NRAS et β-caténine entraîne la formation de mélanome ayant comme origine cellulaire les cellules souches mélanocytaire/cellules s’amplifiant de manière transitoire (Delmas et al., 2007).
Figure 2 : The cooperation of mutations in NRAS and β-catenin leads to the formation of melanoma arising from the melanocyte stem cells/transit amplifying cells (Delmas et al., 2007).

In order to understand/improve prevention, early diagnosis, cellular transformation and therapy, we believe that it is crucial to know better the molecular and cellular mechanisms occurring during the normal and pathological development of this lineage and during melanoma initiation/progression in a cell autonomous and cell non-autonomous manner. Human genetics information associated with the production/study of murine melanoma models will allow for a better understanding of the molecular and cellular events occurring during oncogenesis.

 

In this respect, our general goal is to better understand the cellular and molecular mechanisms associated with the normal and pathological development of melanocytes. This general goal has five main aims :

  1. To better understand the b-catenin signaling during the establishment and renewal of the melanocyte lineage.
  2. To better understand the cooperation between UV and Wnt/b-catenin signaling.
  3. To induce cooperation of signaling pathways during melanomagenesis.
  4. To evaluate the respective importance of MITF and BRN2 during melanoma initiation and progression. 
  5. To produce relevant melanoma models for humans.

Key publications

Year of publication 2018

Pierre Sohier, Léa Legrand, Zackie Aktary, Christine Grill, Véronique Delmas, Florence Bernex, Edouard Reyes-Gomez, Lionel Larue, Béatrice Vergier (2018 May 31)

A histopathological classification system of Tyr::NRAS murine melanocytic lesions: A reproducible simplified classification.

Pigment cell & melanoma research : 423-431 : DOI : 10.1111/pcmr.12677
Pascal Laurent-Gengoux, Valérie Petit, Zackie Aktary, Stuart Gallagher, Luke Tweedy, Laura Machesky, Lionel Larue (2018 May 18)

Simulation of melanoblast displacements reveals new features of developmental migration.

Development (Cambridge, England) : DOI : dev160200
Veronica A Kinsler, Lionel Larue (2018 Jan 31)

The patterns of birthmarks suggest a novel population of melanocyte precursors arising around the time of gastrulation.

Pigment cell & melanoma research : 95-109 : DOI : 10.1111/pcmr.12645
C Grill, L Benzekri, A Rubod, Z Aktary, K Ezzedine, A Taïeb, Y Gauthier, L Larue, V Delmas (2018 Jan 18)

Epidermal melanocytes in segmental vitiligo show altered expression of E-cadherin, but not P-cadherin.

The British journal of dermatology : 1204-1206 : DOI : 10.1111/bjd.16352

Year of publication 2017

Juliette U Bertrand, Valérie Petit, Elke Hacker, Irina Berlin, Nicholas K Hayward, Marie Pouteaux, Evelyne Sage, David C Whiteman, Lionel Larue (2017 Feb 14)

UVB represses melanocyte cell migration and acts through β-catenin.

Experimental dermatology : DOI : 10.1111/exd.13318

Year of publication 2015

F Rambow, A Bechadergue, F Luciani, G Gros, M Domingues, J Bonaventure, G Meurice, J-C Marine, L Larue (2015 Dec 16)

Regulation of melanoma progression through the TCF4/miR-125b/NEDD9 cascade.

The Journal of investigative dermatology : DOI : 10.1016/j.jid.2016.02.803
All publications