Integrated spatial multi-omics delineates fatty acid degradation fuels malignant evolution at the tumour periphery in cervical squamous cell carcinoma

  • EBioMedicine. 2026 May:127:106256. doi: 10.1016/j.ebiom.2026.106256.
Shitong Lin  1 ,  Zhihui Luo  2 ,  Yuting Li  3 ,  Bai Hu  4 ,  Minghan Qu  5 ,  Binghan Liu  1 ,  Canhui Cao  4 ,  Ting Peng  1 ,  Miaochun Xu  1 ,  Yashi Xu  1 ,  Xiaojie Liu  1 ,  Xiaoli Wang  4 ,  Li Li  4 ,  Wencheng Ding  4 ,  Zhenyu Xu  6 ,  Ruizhi Li  6 ,  Jingwei Zhao  2 ,  Jingmin Zhang  7 ,  Lingfang Wang  8 ,  Fang Ren  9 ,  Chaolong Wang  10 ,  Peng Wu  11
Affiliations
  • 1. Department of Obstetrics and Gynaecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, 430022, PR China.
  • 2. Department of Biology and Genetics, The College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, China.
  • 3. Department of Obstetrics and Gynaecology, National Clinical Research Centre for Obstetrics and Gynaecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Department of Obstetrics and Gynaecology, National Clinical Research Centre for Obstetrics and Gynaecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumour Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6. Shanghai Lu Ming Biotech Co., Ltd., Shanghai, China.
  • 7. Hubei Key Laboratory of Agricultural Bioinformatics, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
  • 8. Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynaecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: [email protected].
  • 9. Department of Gynaecology, First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, Henan, China. Electronic address: [email protected].
  • 10. Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 11. Department of Obstetrics and Gynaecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, 430022, PR China. Electronic address: [email protected].
PMID: 42048995 DOI: 10.1016/j.ebiom.2026.106256
Abstract

Background: Cervical squamous cell carcinoma (CSCC) exhibits profound spatial heterogeneity in evolutionary trajectories across distinct tumour foci, yet the underlying mechanisms remain poorly understood.

Methods: In this study, we performed an integrated spatial transcriptomic and metabolomic analysis of six CSCC and two normal cervical samples, supported by single-cell RNA Sequencing (n = 20) and validated in an independent spatial enhanced resolution omics-sequencing cohort (n = 15), to map the spatial tumour architecture and cellular heterogeneity of CSCC. Findings were functionally confirmed using cell lines, patient-derived organoids, and mouse models.

Findings: We identified that tumour foci with high spatial continuity demonstrated elevated Cancer cell purity and exhibited distinct spatial stratification. The peripheral tumour foci (layer 3) exhibited enhanced proliferative capacity and aggressive traits characterised by elevated epithelial-to-mesenchymal transition (EMT) activity compared to core foci (layer 1), which correlated with advanced evolutionary states. A layer 3-specific gene signature predicted poorer overall survival in both the Cancer Genome Atlas (TCGA) and Tongji Hospital (TJH) cohorts. Spatial multi-omics uncovered progressive metabolic reprogramming along the core-to-periphery axis, with activation of fatty acid degradation emerging as a hallmark of layer 3 aggression. Genetic knockdown (HADH, HADHA and ECHS1) and pharmacological inhibition (mitotane and perhexiline) of fatty acid degradation attenuated malignant phenotypes of layer 3, including proliferation and EMT-driven invasion.

Interpretation: Our work establishes spatially resolved activation of the fatty acid degradation as a key evolutionary engine fuelling the malignant phenotypes of peripheral tumour foci, and nominates stratification-targeted metabolic disruption as a spatially promising therapeutic strategy for CSCC.

Funding: Noncommunicable Chronic Diseases-National Science and Technology Major Project (2025ZD0544100), National Natural Science Foundation of China (82372929, 82503148, 32300460, 32400555 and 82472696), China Postdoctoral Science Foundation (2025M772119), Hubei Provincial Natural Science Foundation (JCZRQN202500308).

Keywords
CSCC; EMT; Fatty acid degradation; Spatial metabolomics; Spatial transcriptomics.
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