Skin Microenvironment Could Yield New Melanoma Treatment Options, Study Finds

An investigation of the skin microenvironment in melanoma offers new insights into the role of epidermal keratinocytes in the pathogenesis of skin cancer.

The study, published in the journal Cancers, suggests that targeting keratinocytes might be one avenue by which to stop or slow melanoma.

Corresponding author Jose M. Ayuso, PhD, of the University of Wisconsin-Madison, and colleagues, noted that approximately 100,000 cases of melanoma are diagnosed in the United States each year, causing about 8000 deaths. Cutaneous melanoma is the result of a proliferation of melanocytes, the cells that produce skin pigment. Most such cancers (60%) have a BRAFV600E mutation.

“After an initial burst of proliferation, melanocytes that acquire the oncogenic driver mutation enter a state of growth arrest known as oncogene-induced senescence (OIS),” Ayuso and colleagues wrote.

Most aberrant melanocytic proliferations do not result in cancer, but instead remain benign. However, when OIS breaks down or is bypassed, melanoma can occur. The investigators said a number of mechanisms that appear to be linked with OIS escape or bypass have been identified, such as a loss of the tumor suppressor gene PTEN, which stops senescence in melanocytes with the BRAFV600E mutation.

Another cause of OIS bypass is epigenetic events.

“H3K9 demethylases LSD1 and JMJD2C were shown to not only promote a BRAF oncogene-induced senescence bypass but also reverse senescence and promote cell proliferation,” they wrote.

Yet, while Ayuso and colleagues said melanocyte-intrinsic molecular events have been extensively studied in melanomagenesis, less attention has been paid to the role of the skin microenvironment on OIS escape. The authors therefore sought to investigate the skin microenvironment and keratinocytes in particular, to see what connections they might find between the microenvironment and melanocyte senescence.

The investigators used microscale models to mimic the skin microenvironment, and then monitored the interactions between BRAFV600E melanocytes, keratinocytes, and fibroblasts to better understand their roles in melanomagenesis. The analysis suggested a significant role for keratinocytes.

“We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes,” Ayuso and colleagues wrote. “We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes.”

The authors said their research is important because a better understanding of what helps or hurts senescence might make it possible to develop therapies that promote senescence and thus prevent melanomagenesis.

Ayuso and colleagues also found new insights into why some ethnic populations appear to have higher rates of melanoma. They noted that melanocytes and keratinocytes from donors of patients of white European ancestry and patients of black African ancestry had different interactions.

“[W]hite keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes,” they wrote. “These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis.”

The investigators concluded that additional studies will be needed to better understand the skin microenvironment and how forced changes in the microenvironment might be used to suppress melanoma.

“Such studies could help devise novel strategies for melanoma prevention and reverse the increasing trend of melanoma incidence,” they concluded.

Reference

Sadangi S, Milosavljevic K, Castro-Perez E, et al. Role of the skin microenvironment in melanomagenesis: epidermal keratinocytes and dermal fibroblasts promote BRAF oncogene-induced senescence escape in melanocytes.. Cancers (Basel). 2022;14(5):1233. doi:10.3390/cancers14051233