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Single-Cell Profiling Reveals Conserved Differentiation and Partial EMT Programs Orchestrating Ecosystem-Level
Donghui Jiang1, Xiaoguang Wu1, Yuanyuan Deng2
1Department of Otolaryngology & Head and Neck Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Journal of Cellular and Molecular Medicine
|May 3, 2025
Summary
Head and neck squamous cell carcinoma (HNSC) ecosystems involve distinct epithelial programs. Invasive programs may promote tumor spread by interacting with the microenvironment, while differentiation programs may enhance immune surveillance.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Head and neck squamous cell carcinoma (HNSC) is characterized by significant intratumoral heterogeneity.
- The tumor microenvironment (TME) plays a crucial role in HNSC progression through complex cellular interactions.
Purpose of the Study:
- To define conserved cellular ecosystems within HNSC using single-cell transcriptomics.
- To elucidate the crosstalk between malignant epithelial cells and the TME.
- To identify potential therapeutic targets based on ecosystem-level patterns.
Main Methods:
- Consensus non-negative matrix factorization (cNMF) applied to multi-site HNSC single-cell transcriptomes.
- Compartment-specific crosstalk analysis to identify signaling pathways.
- Multi-compartment correlation analysis to reveal ecosystem-level patterns.
Main Results:
- Six major epithelial programs were identified, including a differentiation-associated program (Epi_Diff) linked to favorable prognosis and an invasive program (Epi_pEMT) associated with extracellular matrix (ECM) remodeling and partial epithelial-mesenchymal transition (EMT).
- Epi_pEMT cells may form pro-invasive niches by interacting with cancer-associated myeloid fibroblasts (mCAF1) and tumor-associated macrophages (TAM(SPP1)).
- Epi_Diff cells may inhibit immune infiltration through interactions with NK/T cells, while ecosystem-level analyses revealed inverse associations between Epi_Diff and Epi_pEMT, mCAF1 and cancer-associated fibroblasts (cCAF), and TAM(SPP1) dominance with TAM(C1Q) and NK/T infiltration.
Conclusions:
- HNSC ecosystems are structured by distinct epithelial programs and their interactions with the TME.
- The balance between invasive and differentiation programs, along with specific immune cell subtypes, may dictate disease progression.
- Understanding these ecosystem dynamics offers potential avenues for targeted therapies in HNSC.
