Mucosal melanoma (MM) is a rare melanoma subtype that originates from melanocytes within sun-protected mucous membranes. Compared with cutaneous melanoma (CM), MM has worse prognosis and lacks effective treatment options. Moreover, the endogenous or exogenous risk factors that influence mucosal melanocyte transformation, as well as the identity of MM precursor lesions, are ambiguous. Consequently, there remains a lack of molecular markers that can be used for early diagnosis, and therefore better management, of MM. In this review, we first summarize the main functions of mucosal melanocytes. Then, using oral mucosal melanoma (OMM) as a model, we discuss the distinct pathologic stages from benign mucosal melanocytes to metastatic MM, mapping the possible evolutionary trajectories that correspond to MM initiation and progression. We highlight key areas of ambiguity during the genetic evolution of MM from its benign lesions, and the resolution of which could aid in the discovery of new biomarkers for MM detection and diagnosis. We outline the key pathways that are altered in MM, including the MAPK pathway, the PI3K/AKT pathway, cell cycle regulation, telomere maintenance, and the RNA maturation process, and discuss targeted therapy strategies for MM currently in use or under investigation.

Oral mucosal wounds exhibit accelerated healing with reduced scarring compared to cutaneous wounds, representing an optimal wound healing paradigm. However, the specific cellular subtypes orchestrating the efficient healing of mucosal tissues remain elusive. Through a comprehensive analysis integrating bulk-mRNA and single-cell sequencing data during the wound healing process in oral mucosa and skin, we have delineated a distinct set of genes markedly upregulated during tissue repair. This collection of wound healing-associated genesets was highly enriched in a specific keratinocyte subpopulation identified as STAT3-activated SPRR1B+ keratinocytes. Notably, despite the inherent rapidity of oral mucosal healing, the induction of SPRR1B+ keratinocytes is evident in both skin and mucosal wound healing processes in murine model. Intriguingly, these wound healing-promoting SPRR1B+ keratinocytes, which are induced via STAT3 activation, inherently abundant in unwounded normal mucosa but absent in normal skin. SPRR1B knockdown significantly inhibits mucosal keratinocyte migration, a critical attribute for effective wound healing. In summary, through analysis of human oral and skin wound healing processes at single-cell resolution, coupled with validation in murine model, suggests STAT3-activated SPRR1B+ keratinocytes are associated with the rapid mucosal repair process. This discovery underscores the potential application of SPRR1B+ keratinocytes in the therapeutic management of chronic or non-healing wounds.

Chromosomal 11q13.3 amplification is the most common gene copy-number variation event in head and neck squamous cell carcinoma (HNSCC) that corresponds with poor prognosis. Although cyclin D1, a G1/S phase cell-cycle regulatory protein at this locus, is considered as a key driver of malignant progression, further exploration is needed to develop more effective targets for cases with this amplification. Using CRISPR-based gene knockout screening of genes located in chr11q13.3, we found that loss of the gene encoding the Fas-associated death domain (FADD) protein, a well-recognized adapter to caspase-8 that induces cell apoptosis, significantly reduced cancer cell proliferation. FADD expression was elevated in chr11q13.3-amplified tumors and correlated with poor prognosis. RNA sequencing, mass spectrometry, and proteomics analyses revealed a direct relationship between FADD and the DNA helicase MCM5 in the S phase. FADD and cyclin D1 acted at different stages of the cell cycle to synergistically induce proliferation, and caspase-8 deficiency was required for the oncogenic activity of FADD. In a patient-derived xenograft model with chr11q13.3 amplification, combined administration of the DNA helicase complex inhibitor and CDK4/6 inhibitor effectively curtailed tumor growth. Overall, this study identified a nonclassic oncogenic role for FADD in mediating tumor progression in HNSCC and provided a feasible treatment option for patients with chr11q13.3 amplification. Significance: FADD promotes progression of tumors with chr11q13.3 amplification by binding to the DNA helicase complex, which can be targeted in combination with cyclin D1 as a viable therapeutic strategy for HNSCC patients.

Mutations in splicing factors are recurrent across human cancers and drive widespread RNA splicing dysregulation. Among these, SF3B1 is the most frequently mutated, yet its hotspot mutations exhibit lineage specificity, with SF3B1 ^R625 mutations predominantly found in melanoma and SF3B1 ^K700E in hematologic malignancies. However, the mechanistic basis for this cancer-type specificity remains unclear. Here, we demonstrate that SF3B1 ^R625H induces greater activation of alternative 3′ splice site than SF3B1 ^K700E . Mechanistically, the polyadenine-enriched sequence surrounding cryptic branch point sites confers SF3B1 ^R625H selective advantage in aberrant splicing. This splicing bias leads to preferential missplicing of NF1 , a RAS inhibitor, resulting in RAS hyperactivation and accelerated melanoma progression in mouse models. This study redefines the oncogenic paradigm of SF3B1 mutations by demonstrating that distinct hotspot mutations exploit lineage-specific splicing vulnerabilities to drive tumorigenesis and establishes RAS activation as key mechanism underlying SF3B1 ^R625H -driven melanoma, positioning RAS pathway as tractable therapeutic target in SF3B1 -mutant melanoma.