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Updated: Aug 19, 2026
Isolation and Characterization of a Head and Neck Squamous Cell Carcinoma Subpopulation Having Stem Cell Characteristics
Published on: May 11, 2016
Single-cell transcriptomic analysis of cutaneous squamous cell carcinoma identifies an NR1H3-associated angiogenic
Yong He1, Ting Tian1, Liming Li1
1Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, China.
Introduction:
Cutaneous squamous cell carcinoma (cSCC) is a common keratinocyte-derived malignancy whose progression is strongly influenced by the tumor microenvironment. Although recent studies have begun to describe cellular diversity in squamous cell carcinomas, the regulatory architecture coordinating epithelial, immune, and stromal interactions in cSCC remains incompletely understood.
Methods:
We performed single-cell RNA sequencing on matched tumor tissues, adjacent normal skin, and peripheral blood from patients with cSCC to construct an integrated cellular landscape of the tumor ecosystem. Lineage trajectory analysis, transcription factor activity inference, and ligand-receptor modeling were used to characterize cellular differentiation, regulatory programs, and intercellular communication within the cSCC microenvironment.
Results:
Analysis of 80,736 single cells revealed extensive heterogeneity across epithelial, immune, and stromal compartments. Trajectory analysis of the myeloid lineage suggested a tumor-associated differentiation continuum extending from circulating monocytes toward a specialized angiogenic macrophage state characterized by transcriptional programs associated with extracellular matrix remodeling and immunoregulatory signaling. Concurrently, malignant keratinocyte populations displayed inferred copy-number alterations and activation of invasive transcriptional programs, accompanied by the emergence of distinct cancer-associated fibroblast subsets associated with stromal remodeling. Ligand-receptor modeling further identified extensive predicted communication networks linking macrophages, fibroblasts, and malignant epithelial cells within the tumor niche. Furthermore, transcription factor activity inference highlighted the nuclear receptor NR1H3 as a candidate regulator associated with the angiogenic macrophage program, and the NR1H3-associated transcriptional signature correlated with poor survival across multiple squamous cell carcinoma cohorts.
Discussion:
These findings define the cellular organization and molecular programs that shape the cSCC microenvironment and provide insights into the coordinated immune, stromal, and epithelial interactions involved in cSCC progression.
