Diagnosing melanoma clinically and under the microscope can be complicated by the presence of melanocytic nevi, otherwise known as birthmarks or moles that are noncancerous. The development of melanoma is a multistep process, where melanocytes mutate and proliferate. Properly identifying melanoma at an early stage is critical for improved survival. A new study recently published by Kiuru et al in the Journal of Investigative Dermatology sheds light on cell type–specific biomarkers of melanoma.
“The 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 author of the study Maija Kiuru, MD, PhD, Associate Professor of Clinical Dermatology and Pathology at UC Davis Health. “To unravel the mystery, we used high-plex spatial RNA profiling to capture distinct gene-expression patterns 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.”
Study Details
The study examined the expression of over 1,000 genes in 134 regions of interest enriched for melanocytes, a type of cell in the skin and eyes that produce 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 NanoString GeoMx® 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 Dr. Kiuru. “Melanoma biomarkers in the epidermis have been largely overlooked in the past.”
Keratinocytes are epidermal cells that have multiple functions, including forming a barrier against micro-organisms, heat, water loss, and ultraviolet radiation. Normal keratinocytes also control the growth of melanocytes.
“Unexpectantly, we discovered that S100A8 is expressed by keratinocytes within the tumor microenvironment during melanoma growth,” said Dr. Kiuru. “We further looked at S100A8 expression in 252 benign and malignant melanocytic tumors, which showed prominent keratinocyte-derived S100A8 expression in melanoma, but not in benign tumors. This suggests that S100A8 expression in the epidermis may be a readily detectable indicator of melanoma development.”
Many molecular tests for diagnosis and prognosis of melanoma are gradually being introduced but markers of early melanoma development, particularly 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 predicting the duration a patient will be cancer-free are largely unknown. Previous research has utilized sophisticated methods, including single-cell RNA sequencing, but has largely focused on melanoma metastases. This has overlooked the keratinocyte microenvironment of primary melanomas.
The study authors concluded, “Together, our results establish a framework for high-plex, spatial, and cell type‒specific resolution of gene expression in archival tissue applicable to the development of biomarkers and characterization of tumor microenvironment interactions in tumor evolution.”
Disclosure: For full disclosures of the study authors, visit jidonline.org.
