Activation of hippo pathway restrains tumor growth in melanoma cells

Melanoma is the most dangerous type of skin cancer due to its ability to grow quickly and spread to any organ. While melanoma accounts for about one percent of all skin cancers, it causes the majority of skin cancer-related deaths, most commonly in people under the age of 30, especially women.

Approximately 30 percent of melanomas begin in existing moles, driven by activating mutations in the MAPK pathway which governs cell growth, proliferation, and survival. Now, researchers have discovered the Hippo tumor suppressor pathway plays a significant role in preventing the transformation of moles into melanoma.

The researchers used human cells and experimental models to demonstrate activation of the kinase BRAF pathway leads to Hippo pathway activation. “When activated, we show the Hippo pathway restrains the growth of melanocytes (melanin-forming cells) and helps prevent their transformation into melanoma,” said lead author. “Similarly, we found that when the Hippo tumor suppressor pathway is suppressed in melanocytes, those cells rapidly go on to form melanoma in multiple experimental models.”

The researchers show that oncogenic BRAF promotes both ERK-dependent alterations in the actin cytoskeleton and whole-genome doubling events, which independently reduce RhoA activity to promote Hippo activation. They also demonstrate that functional impairment of the Hippo pathway enables oncogenic BRAF-expressing melanocytes to bypass nevus formation and rapidly form melanomas.

According to the researchers, discovering the mechanisms our cells employ to protect against tumor formation is key to identifying new drug targets for the successful treatment of cancer. “We hope our study highlights that targeted reactivation of the Hippo pathway is an attractive therapeutic possibility for the future treatment of melanoma,” added corresponding author. 

Although the researchers focused on the role of the Hippo pathway in preventing moles from transformation into melanoma, they believe it is possible the Hippo pathway may be acting similarly in other subtypes of cancer. 

These findings appear in the journal Nature Communications.