PO.BCS01.09 · 生物信息与计算
p-EMT过渡枢纽及其DC2-巨噬细胞生态位定义口腔鳞状细胞癌的复发
p-EMT transitional hub and its DC2-macrophage niche define recurrence in oral squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：部分上皮-间质转化（p-EMT）日益被认为是OSCC侵袭和复发的关键驱动因素，然而维持p-EMT的空间限定生态系统和谱系轨迹仍然未知。
方法：我们使用Xenium 5k空间转录组学分析了来自14例患者的40个肿瘤边缘TMA核心，并整合了两年临床结局（14例非复发，26例复发）。来自8例配对患者（4例非复发，4例复发）的互补snRNA-seq实现了上皮亚聚类、谱系/个体发生建模、配体-受体推断和空间邻域重建。
结果：snRNA-seq揭示了一个明显富集的p-EMT上皮状态（p-EMT_C2），其由ECM重塑基因（MMP11、POSTN、COL11A1）、CAF样标志物（PDGFRB、THY1、FAP）和促侵袭调控因子定义。p-EMT_C2在复发肿瘤中显著扩增。空间映射显示，p-EMT_C2形成一个位于分化的核心上皮和高度侵袭的边缘细胞之间的离散“过渡带”——该区带在复发病灶中优先扩增。拟时序重建表明，p-EMT_C2代表核心到边缘侵袭轨迹上的一个中心分支枢纽，在功能上将上皮分化与边缘侵袭性联系起来。
引人注目的是，p-EMT_C2嵌入在一个由DC2树突状细胞和促转移巨噬细胞亚群（Macrophage_C1）组成的复发特异性多细胞生态位中。这个三细胞生态位在复发核心中表现出强烈的空间共现。Macrophage_C1表达IL1A、IL6、HBEGF、THBS1、VEGFC、DKK1、PTHLH和FOSL1，而DC2细胞则显示出互补的促侵袭特征。配体-受体分析揭示了这三个群体之间密集的相互信号传导，提示DC2和Macrophage_C1协同强化并稳定p-EMT枢纽状态。
结论：我们将p-EMT_C2鉴定为一个在转录和空间上处于中心地位的枢纽，它协调OSCC中从分化上皮到侵袭边缘状态的转变。它与DC2和促转移巨噬细胞的紧密关联定义了一个复发特异性的侵袭生态系统。这些发现提名p-EMT_C2-DC2-巨噬细胞轴为一个具有机制依据的治疗靶点，用于阻断OSCC复发的出现。
查看英文原文 English abstract
Background: Partial epithelial-to-mesenchymal transition (p-EMT) is increasingly recognized as a critical driver of invasion and recurrence in OSCC, yet the spatially defined ecosystems and lineage trajectories that sustain p-EMT remain unknown.
Methods: We analyzed 40 tumor-edge TMA cores from 14 patients using Xenium 5k spatial transcriptomics and integrated two-year clinical outcomes (14 non-recurrence, 26 recurrence). Complementary snRNA-seq from 8 matched patients (4 non-recurrence, 4 recurrence) enabled epithelial subclustering, lineage/ontogeny modeling, ligand-receptor inference, and spatial neighborhood reconstruction.
Results: snRNA-seq uncovered a distinctly enriched p-EMT epithelial state (p-EMT_C2) defined by ECM-remodeling genes (MMP11, POSTN, COL11A1), CAF-like markers (PDGFRB, THY1, FAP), and pro-invasive regulators. p-EMT_C2 was significantly expanded in recurrence tumors. Spatial mapping revealed that p-EMT_C2 forms a discrete “transitional zone” positioned between differentiated core epithelium and highly invasive edge cells-a zone that was preferentially amplified in recurrence lesions. Pseudotime reconstruction demonstrated that p-EMT_C2 represents a central branching hub along the core-to-edge invasion trajectory, functionally linking epithelial differentiation to edge aggressiveness.
Strikingly, p-EMT_C2 was embedded within a recurrence-specific multicellular niche composed of DC2 dendritic cells and a pro-metastatic macrophage subset (Macrophage_C1). This tri-cellular niche exhibited strong spatial co-occurrence in recurrence cores. Macrophage_C1 expressed IL1A, IL6, HBEGF, THBS1, VEGFC, DKK1, PTHLH, and FOSL1, while DC2 cells displayed complementary pro-invasive signatures. Ligand-receptor analysis revealed dense reciprocal signaling among the three populations, suggesting that DC2 and Macrophage_C1 collaboratively reinforce and stabilize the p-EMT hub state.
Conclusions: We identify p-EMT_C2 as a transcriptionally and spatially central hub that orchestrates the transition from differentiated epithelium to invasive edge states in OSCC. Its tight association with DC2 and pro-metastatic macrophages defines a recurrence-specific invasive ecosystem. These findings nominate the p-EMT_C2-DC2-macrophage axis as a mechanistically grounded therapeutic target for disrupting the emergence of recurrence in OSCC.
利益披露 Disclosure
Y. Jin, None..
J. Ji, None..
H. Lee, None..
N. Kim, None..
E. Chung, None.