Multilineage differentiation drives hamartoma formation in large-to-giant congenital melanocytic naevi: evidence for naevocyte multipotency.
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BACKGROUND: Large-to-giant congenital melanocytic naevi (LGCMNs) often develop nodules that contain ectopic tissues (hamartomas), which are rarely observed in small-to-medium congenital melanocytic naevi (SMCMNs). The origin and mechanism of the hamartomas formed in LGCMNs remain unknown. OBJECTIVES: To investigate the origin and mechanism of hamartoma formation in LGCMNs, and to evaluate the stemness and multipotency of LGCMNs. METHODS: A total of 276 congenital melanocytic naevi (CMNs) of different sizes were included in this study. LGCMNs with diverse hamartomas were identified and analysed by histology and immunofluorescence. Whole-exome sequencing (WES) of matched healthy skin, LGCMN and hamartoma tissues assessed mutational overlap. RNA sequencing (RNAseq), immunohistochemistry and immunocytochemistry evaluated multipotency pathways and stem markers across CMN sizes. LGCMN and SMCMN cells were assayed for clonogenicity and induced to differentiate along osteogenic, chondrogenic, adipogenic and neurogenic lineages in vitro. Three-dimensional spheroid cultures and cell-derived xenograft (CDX) models tested LGCMN multilineage differentiation in vivo. Single-cell RNAseq (scRNAseq) of patient-derived hamartomas delineated intermediate differentiation states and active pathways. RESULTS: We found that LGCMN lesions harboured bone, cartilage, adipose and neural hamartomas with intermixed naevocytes. WES revealed 35-92% overlap of somatic mutations (including driver mutations) between LGCMN and hamartoma tissue, indicating a common origin. Immunofluorescence identified cells in hamartoma co-expressing lineage-specific and naevocyte markers, indicating intermediate differentiation states. RNAseq, immunohistochemistry and immunocytochemistry showed that LGCMNs were enriched for multipotency pathways and expressed higher levels of stem cell markers than SMCMNs. LGCMNs showed greater clonogenicity in vitro, and all LGCMNs robustly differentiated into osteocytes, chondrocytes, adipocytes and neuronal cells/astrocytes, whereas SMCMNs or healthy melanocytes largely failed. Intriguingly, in three-dimensional cultures and CDX models, LGCMNs were able to form lineage-specific hamartomas. scRNAseq identified intermediate differentiation clusters that co-expressed melanocytic and multilineage markers, confirming the transdifferentiation. Upregulation of neuroactive ligand-receptor signalling was identified as the common feature during differentiation. CONCLUSIONS: Hamartomas in LGCMNs originate from the LGCMN cells themselves, which undergo multipotent differentiation. LGCMNs have markedly greater stemness and multipotency than SMCMNs. Our data implicate the neuroactive ligand-receptor pathway in mediating LGCMN transdifferentiation. These findings shed light on LGCMN development and suggest that modulating differentiation pathways might offer new therapeutic approaches.