Normal and Pathological Development of Melanocytes

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.

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 : 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.