FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis
Abstract
Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis. Integrated transcriptome, lipidomic, metabolomic, and functional analyses demonstrated that MICs depend on oxidative phosphorylation (OXPHOS) fueled by fatty acid oxidation (FAO) in the lipid-rich LN microenvironment. Mechanistically, the NRF2-SLC7A11 axis promotes glutathione synthesis to mitigate oxidative stress, thereby enhancing stress resistance and metastatic potential of MICs. Inhibition of NRF2-SLC7A11 reduced LN metastasis and sensitized tumors to cisplatin. Clinically, elevated NRF2-SLC7A11 expression was observed in tumors, with high expression correlating with LN metastasis, chemoresistance, and poor prognosis in esophageal squamous cell carcinoma (ESCC). These findings highlight the pivotal roles of FAO-fueled OXPHOS and NRF2 in LN metastasis and suggest targeting these pathways as a promising therapeutic strategy for metastatic ESCC.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Shan-Shan Li
Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital
Baifeng Zhang
Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Cuicui Huang
Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Yuying Fu
Advanced Energy Science and Technology Guangdong Laboratory
Yuying Zhao
Key Lab of Biomass Energy and Material, Jiangsu Province; Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, Institute of Chemical Industry of Forest Products
Lanqi Gong
Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Yanan Tan
Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital
Huali Wang
Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital
Wenqi Chen
Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital
Jie Luo
Yu Zhang
Xiangya Hospital, Central South University Changsha China
Stephanie Ma
Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital
Li Fu
College of Materials and Environmental Engineering, Hangzhou Dianzi University, Hangzhou, China.
Chenli Liu
State Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Jiandong Huang
Huai-Qiang Ju
Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital
Anne Wing-Mui Lee
Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital
Xin-Yuan Guan
Department of Clinical Oncology, The University of Hong Kong