A new study led by UC Davis sheds light on cell type-specific biomarkers, or hallmarks, of melanoma. The research was recently published in the Journal of Investigative Dermatology.
Melanoma, the deadliest common skin cancer, is curable with early diagnosis and treatment. However, diagnosing melanoma clinically and under the microscope can be complicated by what are called melanocytic nevi – otherwise known as birthmarks or moles that are not cancerous. The development of melanoma is a multi-step process where “melanocytes”, or cells in the skin that contain melanin, change and multiply. Correct identification of melanoma at an early stage is critical for improving survival.
“Biomarkers of early melanoma evolution and their origin within the tumor and its microenvironment are a potential key to early diagnosis of melanoma,” said corresponding study author Maija Kiuru, associate professor of clinical dermatology and pathology at UC Davis Health . “To unravel the mystery, we used high-resolution spatial RNA profiling to capture distinct patterns of gene expression across cell types during melanoma development. This approach allows studying the expression of hundreds or thousands of genes without disrupting the native architecture of the tumor.”
New technology used during the study
The study examined the expression of more than 1,000 genes in 134 regions of interest enriched in melanocytes, a cell in the skin and eyes that produces the pigment called melanin, as well as neighboring keratinocytes or immune cells. The tissue examined came from patient biopsies from 12 tumors, ranging from benign to malignant, using the GeoMx® NanoString Digital Spatial Profiler.
“We found that melanoma biomarkers are expressed by specific cell types, some by the tumor cells but others by neighboring cells in the so-called tumor microenvironment. The most striking observation was that S100A8, which is a known melanoma marker thought to be expressed by immune cells, was expressed by keratinocytes that make up the outermost layer of the skin called the epidermis,” said Kiuru. “Biomarkers of melanoma in the epidermis have been largely overlooked in the past.”
Keratinocytes are epidermal cells that have multiple functions, including forming a barrier against microorganisms, heat, water loss, and ultraviolet radiation. Normal keratinocytes also control melanocyte growth.
“Suddenly, we discovered it S100A8 it is expressed by keratinocytes within the tumor microenvironment during melanoma growth,” said Kiuru. “We looked further S100A8 expression in 252 benign and malignant melanocytic tumors, which showed marked keratinocyte origin S100A8 expression in melanoma but not in benign tumors. This suggests that S100A8 expression in the epidermis may be an easily detectable indicator of melanoma development.
Many molecular tests for melanoma diagnosis and prognosis are gradually being introduced, but markers of early melanoma development, especially in the tumor microenvironment, remain lacking. In addition, although the treatment of metastatic melanoma has changed drastically since the development of immune checkpoint inhibitor therapies, biomarkers that predict how long a patient will be cancer-free are largely unknown. Previous research has used sophisticated methods, including single-cell RNA sequencing, but has mostly focused on melanoma metastases or secondary tumor growths. This has bypassed the keratinocyte microenvironment of primary melanomas.
Reference: Kiuru M, Kriner MA, Wong S, et al. High-complexity spatiotemporal RNA profiling reveals cell-type-specific biomarker expression during melanoma development. J. Invest. Dermatology. 2022; 142 (5): 1401-1412.e20. doi: 10.1016/j.jid.2021.06.041
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