Single-cell RNA-seq of nevus-derived melanocytes and matching perilesional skin melanocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE303777 | GEO | 2025/11/03
REPOSITORIES: GEO
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Project description:Single-cell RNA-seq of nevus-derived melanocytes and matching perilesional skin melanocytes
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Project description:Congenital melanocytic nevi (CMN) and common acquired melanocytic nevi (AMN) are skin conditions that result from an excess of melanocytes arising during fetal development or detected postnatally. Appropriately weighted whole-genome methylation analysis can be used as a basis for further research in dermatopathology and, in this application, provides new insights into nevus biology.
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Project description:Melanocytes within benign human nevi are the paradigm for tumor suppressive senescent cells in a pre-malignant neoplasm. These cells typically contain mutations in either the BRAF or N-RAS oncogene and express markers of senescence, including p16. However, a nevus can contain 10s to 100s of thousands of clonal melanocytes and approximately 20-30% of melanoma are thought to arise in association with a pre-existing nevus. Neither observation is indicative of fail-safe senescence-associated proliferation arrest and tumor suppression. We set out to better understand the status of nevus melanocytes. Proliferation-promoting Wnt target genes, such as cyclin D1 and c-myc, were repressed in oncogene-induced senescent melanocytes in vitro, and repression of Wnt signaling in these cells induced a senescent-like state. In contrast, cyclin D1 and c-myc were expressed in many melanocytes of human benign nevi. Specifically, activated Wnt signalling in nevi correlated inversely with nevus maturation, an established dermatopathological correlate of clinical benignancy. Single cell analyses of lone epidermal melanocytes and nevus melanocytes showed that expression of proliferation-promoting Wnt targets correlates with prior proliferative expansion of p16-expressing nevus melanocytes. In a mouse model, activation of Wnt signaling delayed, but did not bypass, senescence of oncogene-expressing melanocytes, leading to massive accumulation of proliferation-arrested, p16-positive non-malignant melanocytes. We conclude that clonal hyperproliferation of oncogene-expressing melanocytes to form a nevus is facilitated by transient delay of senescence due to activated Wnt signaling. The observation that activation of Wnt signaling correlates inversely with nevus maturation, an indicator of clinical benignancy, supports the notion that persistent destabilization of senescence by Wnt signaling contributes to the malignant potential of nevi. We used RNA-Seq to detail the global programme of gene expression in primary human melanocytes which were Uninfected and BRAF600V induced cells
2013-08-01 | E-GEOD-46805 | biostudies-arrayexpress
Project description:Melanocytes within benign human nevi are the paradigm for tumor suppressive senescent cells in a pre-malignant neoplasm. These cells typically contain mutations in either the BRAF or N-RAS oncogene and express markers of senescence, including p16. However, a nevus can contain 10s to 100s of thousands of clonal melanocytes and approximately 20-30% of melanoma are thought to arise in association with a pre-existing nevus. Neither observation is indicative of fail-safe senescence-associated proliferation arrest and tumor suppression. We set out to better understand the status of nevus melanocytes. Proliferation-promoting Wnt target genes, such as cyclin D1 and c-myc, were repressed in oncogene-induced senescent melanocytes in vitro, and repression of Wnt signaling in these cells induced a senescent-like state. In contrast, cyclin D1 and c-myc were expressed in many melanocytes of human benign nevi. Specifically, activated Wnt signalling in nevi correlated inversely with nevus maturation, an established dermatopathological correlate of clinical benignancy. Single cell analyses of lone epidermal melanocytes and nevus melanocytes showed that expression of proliferation-promoting Wnt targets correlates with prior proliferative expansion of p16-expressing nevus melanocytes. In a mouse model, activation of Wnt signaling delayed, but did not bypass, senescence of oncogene-expressing melanocytes, leading to massive accumulation of proliferation-arrested, p16-positive non-malignant melanocytes. We conclude that clonal hyperproliferation of oncogene-expressing melanocytes to form a nevus is facilitated by transient delay of senescence due to activated Wnt signaling. The observation that activation of Wnt signaling correlates inversely with nevus maturation, an indicator of clinical benignancy, supports the notion that persistent destabilization of senescence by Wnt signaling contributes to the malignant potential of nevi.
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Project description:A substantial part of cutaneous malignant melanomas develops from benign nevi. However, the precise molecular events driving the transformation from benign to malignant melanoma are not well understood. We used laser microdissection and mass spectrometry to analyze the proteomes of melanoma subtypes, including superficial spreading melanomas (SSM, n=17), nodular melanomas (NM, n=17), and acral melanomas (AM, n=15). Furthermore, we compared the proteomes of nevi cells and melanoma cells within the same specimens (nevus-associated melanoma (NAM, n=14)). In total, we quantified 7,935 proteins. Despite the genomic and clinical differences of the melanoma subtypes, our analysis revealed relatively similar proteomes, except for the upregulation of proteins involved in immune activation in NM vs AM. Examining NAM versus nevi, we found 1,725 differentially expressed proteins. Among these proteins were 140 that overlapped with cancer hallmarks, tumor suppressors, and regulators of metabolism and cell cycle. Pathway analysis indicated aberrant activation of the RAS/MAPK and PI3K-AKT-mTOR pathways, as well as the Hippo-YAP pathway. Using a classifier, we identified six proteins capable of distinguishing melanoma from nevi samples. Our study represents the first comprehensive comparative analysis of the proteome in melanoma subtypes and associated nevi, offering new insights into the biological behavior of these distinct entities.
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Project description:BRAFV600E-induced cell growth arrest in melanocytic nevus is on debate where only one third of melanomas arise directly from nevi. We showed that simultaneous neonatal oncogene (BRAFV600E) activation and UVB irradiation prevent BRafV600E-induced growth arrest in melanocytes, allowing melanoma development. A meta-analysis of gene expression profiles of melanocytes isolated from different mouse models and numerous studies revealed multiple common genes and processes involved in preventing BRafV600E-induced growth arrest. In humans, many of these genes are associated with poor survival and are upregulated during melanoma progression and in many RAS pathway activation-driven tumors. Single-cell profiling confirmed that BRAFV600E and the identified genes cooperate in melanocyte transformation, including the acquisition of multidrug resistance features. Depletion of these genes in vitro and in vivo revealed the utility of the encoded proteins as therapeutic targets. These results support the existence of BRAFV600E-mutated melanomas unassociated with nevus progression and identify targets for melanoma treatment.
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Project description:Malignant melanoma might develop from melanocytic nevi in which the growth-arrested state has been broken. We analyzed the gene expression of young and senescent human melanocytes in culture. In this dataset we include the expression data of young and senescent human melanocytes.
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Project description:Acquired melanocytic nevi grow and persist in a stable form into adulthood. Using genome-wide methylation profiling, we evaluated 32 histopathologically confirmed, and dermoscopically characterized nevi, with matched adjacent skin, to identify key epigenetic regulatory mechanisms involved in nevogenesis. Benign (n=13; 69% globular and 31% non-specific dermoscopic pattern) and dysplastic (n=19; 95% reticular/nonspecific dermoscopic pattern) nevi were dissimilar with only two shared differentially methylated (DM) loci. Relative to adjacent skin, benign nevi demonstrated an increase in both genome-scale methylation and methylation of Alu/LINE-1 retrotransposable elements, a marker of genomic stability, as well as global methylation. In contrast, dysplastic nevi showed evidence for genomic instability via hypomethylation of Alu/LINE-1. The difference in methylation between benign and dysplastic nevi was statistically significant for Alu (P = 0.00019) and LINE-1 (P = 0.000035) retrotransposable elements. Using dermoscopic classifications, reticular/nonspecific nevi had 59,572 CpG DM loci (Q < 0.05), whereas globular nevi had non-significant DM loci. The relative activity of reticular/non-specific nevi was evidenced by 50,720 hypomethylated loci being enriched for accessible chromatin, and 8,852 hypermethylated loci strongly enriched, for example, marks of active gene promoters, which suggests that gain of DNA methylation observed in these nevus types plays a role in gene regulation.
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