RESEARCHERS LEARN MORE ABOUT THE PTEN GENE’S ROLE IN MELANOMA

Source: InstitutCurie, September 2015

Lionel Larue and his team are boosting our understanding of the PTEN gene’s role in melanoma, a very aggressive form of skin cancer. Mutations resulting in the loss of PTEN expression are commonly found in many forms of cancer and are associated with metastasis. However, we still know little about how these mutations occur within the cell.

Melanocytes are the cells responsible for skin pigmentation. Temporary, uncontrolled melanocyte growth results in the formation of beauty spots, within which the melanocytes rest and remain harmless. “34% of melanomas involve a loss of PTEN, compared to just 5% of beauty spots, which are considered one of the benign precursors for this type of cancer,” explains Lionel Larue, Inserm Director of Research and a melanoma specialist. “Our team, Normal and Pathological Development of Melanocytes (CNRS/Inserm), has found that the loss of PTEN increases the likelihood that benign forms of melanoma will become malignant, and has also described the mechanisms used by PTEN to control this process.”

Waking sleeping melanocytes

The loss of PTEN wakes up the resting cells and transforms them into aggressive melanomas that can multiply, migrate and invade distant organs. But how exactly does the loss of PTEN transform these cells? “We observed that PTEN causes the ?-catenin protein in the membrane to localise into the cell nucleus,” says Larue. The team’s previous work showed that ?-catenin can be found localised in the nucleus of melanoma cells. Depending on the condition of the cell and the level of ?-catenin activation, the presence of this protein within the nucleus can have protective effects, by inhibiting cell growth and migration, and/or destructive effects, by triggering melanoma growth and metastasis. The next step is to understand how PTEN loss impacts on the nuclear localisation of ?-catenin and the related cellular mechanisms.

Enter CAV1…

In their search for a molecule responsible for relocating ?-catenin within the cell, the researchers identified scaffolding protein CAV1. “The interaction network we discovered as a result is very complex,” adds Larue. “It is based on interaction loops between three proteins: PTEN, ?-catenin and CAV1.”

The mutations that inactivate PTEN lead, via CAV1, to the physical separation of beta-catenin from a transmembrane protein called E-cadherin. Together, these two proteins act as a glue that sticks cells together, preventing them from disseminating. Splitting beta-catenin and E-cadherin apart therefore has serious consequences: it can trigger the development of metastasis. In addition to definitively answering the long-controversial question of CAV1’s role in melanoma development, this discovery reveals that CAV1 is a potential target for blocking tumour progression.

Since it is metastasis that makes melanoma so dangerous, the discovery is an important step forward in research into and the fight against this form of skin cancer, and potentially other metastatic cancers in which PTEN is involved. Remember: over 1500 people die from melanoma every year in France.