Classification of node-positive melanomas into prognostic subgroups using keratin, immune, and melanogenesis expression patterns

Abstract

Cutaneous melanoma tumors are heterogeneous and show diverse responses to treatment. Identification of robust molecular biomarkers for classifying melanoma tumors into clinically distinct and homogenous subtypes is crucial for improving the diagnosis and treatment of the disease. In this study, we present a classification of melanoma tumors into four subtypes with different survival profiles based on three distinct gene expression signatures: keratin, immune, and melanogenesis. The melanogenesis expression pattern includes several genes that are characteristic of the melanosome organelle and correlates with worse survival, suggesting the involvement of melanosomes in melanoma aggression. We experimentally validated the secretion of melanosomes into surrounding tissues by melanoma tumors, which potentially affects the lethality of metastasis. We propose a simple molecular decision tree classifier for predicting a tumor’s subtype based on representative genes from the three identified signatures. Key predictor genes were experimentally validated on melanoma samples taken from patients with varying survival outcomes. Our three-pattern approach for classifying melanoma tumors can contribute to advancing the understanding of melanoma variability and promote accurate diagnosis, prognostication, and treatment.

Low expression of endoplasmic reticulum stress-related gene SERP1 is associated with poor prognosis and immune infiltration in skin cutaneous melanoma

“…This is consistent with the GO and KEGG enrichment analysis of SERP1 in patients with SKCM in our study. Additionally, the predicted genes used in the study to validate the keratin group, including IVL and SPRR1B [ 28 ], are consistent with the hub genes of DEGs from cytoHubba and MCODE in our analysis. Thus, keratinization, epidermis development, and cornification related to SERP1 are likely to play an important role in the tumorigenesis and prognosis of SKCM.…”

“…Early stage SKCM has a better prognosis after surgical resection; however, SKCM tends to subcutaneously metastasize to regional lymph nodes and distant organs, which complicated treatment for advanced stages [ 27 ]. Netanely et al [ 28 ] divided melanoma tumors into four subtypes according to different gene expression signatures and validated the classification. They found that the keratin group has the lowest survival rate, significantly higher Breslow depths, and higher pathologic T values.…”

Lipid droplets are a metabolic vulnerability in melanoma

“…This state has translational importance, since clinical data has correlated differentiated melanocytic identity with worse clinical outcomes [16][17][18][19] . Acquisition of a differentiated melanocytic cell identity has been associated with metastatic seeding and evasion to targeted therapy in patients, highlighting the need to uncover vulnerabilities in this cell state 19,20 . Dissecting the mechanisms driving this state requires tractable genetic models that recapitulate human melanoma phenotypic heterogeneity while preserving an immunocompetent TME.…”

Exploring Tumor Immune Microenvironment and Its Associations With Molecular Characteristics in Melanoma

“…In addition, TIGIT, which is a T-cell immune receptor with Ig and ITIM domains ( 31 ) and was upregulated in the high-immunity, has been recently identified as an attractive cancer immunotherapy target, because of its key role in interactions between the cells within the tumor microenvironment. The down-regulated genes were enriched in cornification, epidermis development, and keratin-related process ( Figure 2G ), all of which are associated with forming the outermost skin barrier ( 32 ). For example, human tissue kallikreins 7 (hKLK7) takes part in skin desquamation, which has been involved in keratinocyte cell shedding to catalyze the degradation of intercellular cohesive structures at the skin surface ( 33 ).…”