Melanoma in Pediatric and Young Adult Patients.

PURPOSE OF REVIEW: Melanoma in younger individuals has different clinical presentations, histologic characteristics and prognosis from older patients. This review summarizes key differences and important new insights into pediatric and young adult melanoma, as well as recent evolutions in treatment. RECENT FINDINGS: Molecular techniques have improved the classification of melanocytic neoplasms, and are especially useful in the workup of the diagnostically challenging lesions frequent in this age group. Molecular evaluation highlights differences between melanoma and atypical lesions with Spitz-like morphology, and should routinely be incorporated for diagnosing and classifying Spitzoid melanocytic to guide prognostication and treatment. Once diagnosed, the management of bona fide melanoma in children and young adults is largely similar to older patients, while the optimal management of lesions such as atypical Spitz tumors remains uncertain. Increased awareness of the presentation and diagnostic characteristics of melanoma in young individuals will allow earlier detection, and improved diagnostic techniques will allow optimum management without over- or under-treatment.

Differential histone acetylation and super-enhancer regulation underlie melanoma cell dedifferentiation.

Dedifferentiation or phenotype switching refers to the transition from a proliferative to an invasive cellular state. We previously identified a 122-gene epigenetic gene signature that classifies primary melanomas as low versus high risk (denoted as Epgn1 or Epgn3). We found that the transcriptomes of the Epgn1 low-risk and Epgn3 high-risk cells are similar to the proliferative and invasive cellular states, respectively. These signatures were further validated in melanoma tumor samples. Examination of the chromatin landscape revealed differential H3K27 acetylation in the Epgn1 low-risk versus Epgn3 high-risk cell lines that corroborated with a differential super-enhancer and enhancer landscape. Melanocytic lineage genes (MITF, its targets and regulators) were associated with super-enhancers in the Epgn1 low-risk state, whereas invasiveness genes were linked with Epgn3 high-risk status. We identified the ITGA3 gene as marked by a super-enhancer element in the Epgn3 invasive cells. Silencing of ITGA3 enhanced invasiveness in both in vitro and in vivo systems, suggesting it as a negative regulator of invasion. In conclusion, we define chromatin landscape changes associated with Epgn1/Epgn3 and phenotype switching during early steps of melanoma progression that regulate transcriptional reprogramming. This super-enhancer and enhancer-driven epigenetic regulatory mechanism resulting in major changes in the transcriptome could be important in future therapeutic targeting efforts.

Androgen drives melanoma invasiveness and metastatic spread by inducing tumorigenic fucosylation.

Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveal that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic capacity. Tumor microarray and gene expression analyses demonstrate that AR-FUT4-L1CAM-AJs signaling correlates with pathological staging in melanoma patients. By delineating key androgen-triggered signaling that enhances metastatic aggressiveness, our findings help explain sex-associated clinical outcome disparities and highlight AR/FUT4 and its effectors as potential prognostic biomarkers and therapeutic targets in melanoma.

Pre-existing skin-resident CD8 and gd T cell circuits mediate immune response in Merkel cell carcinoma and predict immunotherapy efficacy.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL-1. Responders have increased type I/II interferons and pre-existing tissue resident (Trm) CD8 or Vd1 gd T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs. Spatial transcriptomics demonstrated co-localization of T cells with B and dendritic cells, which supply chemokines and co-stimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vd1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC.