Tian Jie, Zhang Lu, Zhuang Le, Lin Pingping, Zhang Shenxi, Yan Yicen, Yang Yu, Zhang Guohong, Li Hang, Lai Binbin
Department of Dermatology and Venereology, Peking University First Hospital, Beijing, China.
Institute of Medical Technology, Peking University Health Science Center, Beijing, China.
Theranostics. 2025 Mar 3;15(9):3900-3923. doi: 10.7150/thno.99526. eCollection 2025.
Intratumor heterogeneity in plantar melanoma orchestrates transcriptional programs that contribute to resistance to target- and immuno-therapies. However, the evolution and spatial distribution of cellular subgroups, as well as their effects on immune environment and patient prognosis, remain unclear. We analyzed 218,021 cells from 20 plantar melanoma and 6 normal samples using single-cell RNA sequencing to reveal the evolutionary characteristics and communication patterns of tumor subgroups. Spatial transcriptomics and multiplex immunohistochemistry (mIHC) were used to map the spatial distribution of these subgroups, with mIHC scores further evaluating their correlation with patient prognosis. Single-cell multiomics analysis identified key transcription factors associated with chromatin accessibility. In addition, survival analysis was performed using bulk RNA sequencing data from 68 melanoma patients. We identified a continuum of subgroups originating from stem cells via transitional and Schwann cell-like precursor states, ultimately reaching a Schwann cell-like state. This evolution trajectory was supported by integrative evidence, including assessments of stemness, transitional states, RNA velocity, and transcription factors. The histological distribution of these subgroups was validated by spatial transcriptomics and multiple IHC. Notably, Schwann cell-like subgroup, regulated by transcription factor , was associated with immune cell dysregulation and a worse prognosis, including increased invasion and lymph node metastasis. Mechanically, inhibition of expression blocked the transition to Schwann-like melanoma fate. This study reveals the unique evolutionary trajectory of plantar melanoma, showing its differentiation towards a Schwann-like fate regulated by , leading to a decline in pigment function, enhanced immune tolerance and an increased propensity for lymph node metastasis.
足底黑色素瘤的肿瘤内异质性协调转录程序，这些程序有助于对靶向治疗和免疫治疗产生抗性。然而，细胞亚群的进化和空间分布，以及它们对免疫环境和患者预后的影响仍不清楚。我们使用单细胞RNA测序分析了来自20个足底黑色素瘤和6个正常样本的218,021个细胞，以揭示肿瘤亚群的进化特征和通讯模式。空间转录组学和多重免疫组化（mIHC）被用于绘制这些亚群的空间分布，mIHC评分进一步评估它们与患者预后的相关性。单细胞多组学分析确定了与染色质可及性相关的关键转录因子。此外，使用来自68名黑色素瘤患者的批量RNA测序数据进行了生存分析。我们确定了一个连续的亚群，它们从干细胞通过过渡性和雪旺细胞样前体状态起源，最终达到雪旺细胞样状态。这一进化轨迹得到了综合证据的支持，包括对干性、过渡状态、RNA速度和转录因子的评估。这些亚群的组织学分布通过空间转录组学和多重免疫组化得到了验证。值得注意的是，受转录因子调控的雪旺细胞样亚群与免疫细胞失调和更差的预后相关，包括侵袭增加和淋巴结转移。从机制上讲，抑制表达阻断了向雪旺样黑色素瘤命运的转变。这项研究揭示了足底黑色素瘤独特的进化轨迹，表明其向由调控的雪旺样命运分化，导致色素功能下降、免疫耐受性增强和淋巴结转移倾向增加。
