Abstract 1484: p-EMT transitional hub and its DC2-macrophage niche define recurrence in oral squamous cell carcinoma

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. Citation Format: Yongjoon Jin, Jeong-Yeon Ji, Hyojung Lee, Na-yeon Kim, Eun-Jae Chung, Jong-Il Kim. p-EMT transitional hub and its DC2-macrophage niche define recurrence in oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1484.