Beta-catenin inhibits melanocyte migration but induces melanoma metastasis.
The canonical Wnt signalling pathway induces the β-catenin/lymphoid enhancer factor transcription factors. It is activated in various cancers, most characteristically carcinomas, in which it promotes metastatic spread by increasing migration and/or invasion. The Wnt/β-catenin signalling pathway is frequently activated in melanoma, but the presence of β-catenin in the nucleus does not seem to be a sign of aggressiveness in these tumours. We found that, unlike its positive role in stimulating migration and invasion of carcinoma cells, β-catenin signalling decreased the migration of melanocytes and melanoma cell lines. In vivo, β-catenin signalling in melanoblasts reduced the migration of these cells, causing a white belly-spot phenotype. The inhibition by β-catenin of migration was dependent on MITF-M, a key transcription factor of the melanocyte lineage, and CSK, an Src-inhibitor. Despite reducing migration, β-catenin signalling promoted lung metastasis in the NRAS-driven melanoma murine model. Thus, β-catenin may have conflicting roles in the metastatic spread of melanoma, repressing migration while promoting metastasis. These results highlight that metastasis formation requires a series of successful cellular processes, any one of which may not be optimally efficient.
Centre de Recherche, Developmental Genetics of Melanocytes, Institut Curie, Orsay, France.
S J
SJ
Gallagher
F
F
Rambow
M
M
Kumasaka
D
D
Champeval
A
A
Bellacosa
V
V
Delmas
L
L
Larue
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002465:Cell Movement; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D008544:Melanocytes / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D009368:Neoplasm Transplantation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
C497234:MITF protein, human; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; D051176:beta Catenin; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human