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The Road to Immortality

Understanding the physiopathology of melanoma is crucial for developing alternative treatments,” says Lionel Larue, head of the team that recently identified a molecular mechanism underlying one of the crucial steps of a melanoma’s formation: the cells’ passage into immortality.1,2
With reported cases doubling in the past decade, melanoma is now the fastest growing type of cancer in Western countries. So far, surgery has been the only treatment option to eliminate the tumor. If not effective, metastases can invade vital organs like the liver, lungs, or brain, in which cases chances of survival are slim.
Melanoma is a cancer that affects melanocytes–the melanin-producing skin cells. At least two independent cellular processes must occur for the cancer to become malignant: proliferation and immortalization. Proliferation is triggered by genetic mutations that result in melanocytes multiplying randomly. But most cells usually reach a state of “senescence”: They stop proliferating, forming a benign “beauty spot.”
The tumor becomes malignant when a second phenomenon is added: the inactivation of a tumor-suppressing gene called p16. This enables cells to bypass senescence and become immortal. This gene inactivation can be due to mutations in the gene itself, but other mechanisms can also be involved, as Larue and his colleagues revealed in their study.
The researchers discovered that the stabilized expression of a protein called ß-catenin can repress p16’s expression. Previous studies had shown that ß-catenin triggers proliferation in other types of cancers. This is why the team decided to investigate its implication in proliferation and immortalization in melanoma. To their surprise, transgenic mice expressing stabilized ß-catenin did not trigger proliferation but repressed p16’s expression, triggering immortalization instead.
When they created transgenic mice expressing at the same time a mutation known to trigger proliferation and a stable form of
ß-catenin, the researchers observed that both pathways worked in synergy to develop melanoma.
“The activation of the signaling pathway leading to a stable expression of ß-catenin occurs in 30% of melanomas, which is far from negligible,” notes Larue.
Clémentine Wallace

Notes :

1. Laboratoire Génétique du Développement des Mélanocytes (CNRS / Institut Curie).
2. V. Delmas et al., “Beta-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development,” Genes Dev. 21: 2923-35. 2007.

Contacts :

Lionel Larue
Institut Curie, Orsay.


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