Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide, and lymph node metastasis and distant metastasis are major causes of poor patient prognosis. Clinically, some patients already present with metastasis at the time of diagnosis, and even after surgery, chemoradiotherapy, or comprehensive treatment, they still face the risks of recurrence, metastasis, and treatment failure. Accurately understanding how tumor cells change their states during metastasis has therefore become an important scientific question for improving precision diagnosis and treatment of HNSCC. For a long time, tumor metastasis has been closely associated with epithelial-mesenchymal transition (EMT), in which tumor cells shift from a relatively stable epithelial state to a mesenchymal state with stronger migratory and invasive capacities. However, cellular states in real tumors are far more complex than this “switch-like” model. Increasing evidence suggests that tumor cells may exist in hybrid epithelial-mesenchymal states, or even undergo deeper “cellular identity reshaping” during metastasis. Nevertheless, in HNSCC, which cells first initiate this identity transition, where they evolve, and what molecular mechanisms drive this process remain to be systematically clarified.
Recently, the team led by Prof. Zhigang Cai, Assoc. Prof. Shang Xie, and Prof. Xiaofeng Shan from Peking University School and Hospital of Stomatology published a research article entitled “Precision Omic Portrait Deciphers the Epigenetic Variable during Cellular Identity Reshaping of Metastatic Head and Neck Squamous Cell Carcinoma” in Science Bulletin. Focusing on the clinical challenge of HNSCC metastasis, this study integrated single-cell sequencing, spatial transcriptomics, organoid models, animal experiments, epigenomic profiling, and clinical cohort analyses to systematically depict the cellular evolutionary landscape of metastatic HNSCC. The study further revealed WDR54 as a key epigenetic regulator that initiates tumor-cell identity reshaping.
By integrating single-cell data from primary lesions, lymph node metastases, and distant metastases, the research team constructed a “pan-metastatic” cellular atlas of HNSCC. The study found that tumor metastasis is not driven simply by enhanced cellular migratory ability, but is accompanied by profound cellular identity reshaping. Specifically, a subset of SCGB3A1⁺ malignant epithelial cells may undergo partial EMT (pEMT) during metastasis and progressively acquire CAF-like features, suggesting that tumor cells may participate in remodeling a pro-metastatic microenvironment through “identity rewriting.” Further analyses identified WDR54 as a key molecule that initiates this cellular identity reshaping process. WDR54 was significantly upregulated in malignant HNSCC tissues and was closely associated with metastatic progression, invasive patterns, and poor prognosis. Functional experiments showed that WDR54 maintains tumor-cell lineage plasticity and enhances migration, invasion, and immune evasion, making it an important regulator of HNSCC metastatic progression.
Mechanistically, WDR54 selectively regulates histone modifications such as H3K4me3 and H4K16ac, thereby enhancing chromatin accessibility in regions associated with the TGF-β pathway and pEMT-related genes and initiating the TGF-β-mediated pEMT program. These findings suggest that WDR54 does not merely promote tumor-cell proliferation; rather, it acts as a “molecular spark” of cellular identity reshaping, driving tumor cells into a state with greater plasticity and metastatic potential. The study also highlights the translational potential of WDR54. High WDR54 expression indicates stronger invasiveness and poorer prognosis, while it may also be associated with sensitivity to certain chemotherapeutic agents. These findings provide a new basis for prognostic assessment, therapeutic stratification, and precision intervention in patients with HNSCC.
In summary, this study systematically reveals a cellular identity reshaping axis during HNSCC metastasis and, for the first time, proposes that WDR54 initiates TGF-β-mediated pEMT through epigenetic regulation. This discovery expands current understanding of HNSCC metastasis and provides a new theoretical foundation for early identification, risk assessment, and targeted therapeutic strategy development in metastatic head and neck squamous cell carcinoma.
This study was completed by the Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology. Master’s student Qiushi Feng and Prof. Xiaofeng Shan are co-first authors. Prof. Zhigang Cai and Assoc. Prof. Shang Xie are co-corresponding authors. This work was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.
Science Bulletin
Experimental study