Enhancer Reprogramming Reveals the Tumorigenic Role of PTPRZ1 in Lung Squamous Cell Carcinoma

Lung squamous cell carcinoma (LUSC) remains a lethal malignancy with limited therapeutic advancements, underscoring the need to identify novel oncogenic drivers. This study integrates multi-omics analyses—including ChIP-seq, bulk RNA-seq, single-cell ATAC/RNA-seq, and spatial transcriptomics—to delineate enhancer-driven transcriptional networks in 59 matched LUSC tumors and adjacent normal tissues. The analyses identify 3,447 tumor-specific oncogenic enhancers (SOEs) enriched for master transcription factors (SOX2, TP63, KLF5, GRHL2) that orchestrate malignant programs. Single-cell epigenomic profiling reveals these SOEs to be exclusively active in a cancer cell-like cluster, pinpointing PTPRZ1, a receptor tyrosine phosphatase, as a top SOE-driven candidate. Functional studies demonstrate that PTPRZ1 is essential for LUSC-tumorigenesis and tumor cells proliferation and migration in vitro and in vivo. Spatial transcriptomic analysis further implicates midkine (MDK) as the ligand activating PTPRZ1 in LUSC tumor tissue. Mechanistically, PTPRZ1 mediates MDK-induced PI3K phosphorylation that is essential for LUSC tumor growth. This work illustrates enhancer addiction as a hallmark of LUSC, identifies the PTPRZ1-MDK axis as an important targetable pathway, and establishes a paradigm for dissecting epigenetic vulnerabilities in solid tumors through multi-omics integration. These findings advance precision oncology strategies for LUSC, bridging epigenomic dysregulation to therapeutic intervention. © 2025 The Author(s). Advanced Science published by Wiley-VCHGmbH.