Abstract

Skin cutaneous melanoma (SKCM) is a highly aggressive and resistant cancer with immense metabolic heterogeneity. Here, we performed a comprehensive examination of the diverse metabolic signatures of SKCM based on non-negative matrix factorization (NMF) categorization, clustering SKCM into three distinct metabolic subtypes (C1, C2, and C3). Next, we evaluated the metadata sets of the metabolic signatures, prognostic values, transcriptomic features, tumor microenvironment signatures, immune infiltration, clinical features, drug sensitivity, and immunotherapy response of the subtypes and compared them with those of prior publications for classification. Subtype C1 was associated with high metabolic activity, low immune scores, and poor prognosis. Subtype C2 displayed low metabolic activity, high immune infiltration, high stromal score, and high expression of immune checkpoints, demonstrating the drug sensitivity to PD-1 inhibitors. The C3 subtype manifested moderate metabolic activity, high enrichment in carcinogenesis-relevant pathways, high levels of CpG island methylator phenotype (CIMP), and poor prognosis. Eventually, a 90-gene classifier was produced to implement the SKCM taxonomy and execute a consistency test in different cohorts to validate its reliability. Preliminary validation was performed to ascertain the role of SLC7A4 in SKCM. These results indicated that the 90-gene signature can be replicated to stably identify the metabolic classification of SKCM. In this study, a novel SKCM classification approach based on metabolic gene expression profiles was established to further understand the metabolic diversity of SKCM and provide guidance on precisely targeted therapy to patients with the disease.

Highlights

  • Skin cutaneous melanoma (SKCM) is the deadliest type of skin cancer due to its high metabolic and metastatic rates, accounting for more than 80% of skin cancer-related deaths (Guy et al, 2015; Bolick and Geller, 2021)

  • In The Cancer Genome Atlas (TCGA)-SKCM cohort, the results showed a significantly higher overall survival (OS) in C2 than in C1 and C3, and the same survival differences were verified in the Gene Expression Omnibus (GEO) validation dataset (GSE65904 and GSE54467)

  • With the current widespread use of immune checkpoint inhibitors (ICIs) in clinical trials and for the treatment of advanced melanoma (Woods et al, 2016), we explored the correlation between the expression of 13 classically targeted immune checkpoint genes in these subtypes, which are currently based on immunotherapy inhibitors in clinical trials or licensed for certain cancer types

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Summary

Introduction

Skin cutaneous melanoma (SKCM) is the deadliest type of skin cancer due to its high metabolic and metastatic rates, accounting for more than 80% of skin cancer-related deaths (Guy et al, 2015; Bolick and Geller, 2021). The response of patients with SKCM to immunotherapy is heterogeneous, with approximately 50% of them experiencing unfavorable responses (Robert et al, 2011; Schadendorf et al, 2015). SKCM has been classified into four genomic subtypes, BRAF subtype, RAS subtype, NF1 subtype, and triple wild type based on the somatic mutations in these genes and their ratios (2015). These intrinsic oncogenes contribute to the metabolic conversion of SKCM, which leads to a high degree of plasticity and adaptation of melanoma to unfavorable conditions (Ratnikov et al, 2017). The transformed metabolic microenvironment can reprogram the function of immune cell subpopulations, allowing melanoma to evade the immune system (Bristot et al, 2020)

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