Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC
Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen
Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen
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Research Article Oncology

Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC

Abstract

Cancer stem-like cells (CSCs) are critically involved in cancer metastasis and chemoresistance, acting as one major obstacle in clinical practice. While accumulating studies have implicated the metabolic reprogramming of CSCs, mitochondrial dynamics in such cells remain poorly understood. Here we pinpointed OPA1hi with mitochondrial fusion as a metabolic feature of human lung CSCs, licensing their stem-like properties. Specifically, human lung CSCs exerted enhanced lipogenesis, inducing OPA1 expression via transcription factor SAM Pointed Domain containing ETS transcription Factor (SPDEF). In consequence, OPA1hi promoted mitochondrial fusion and stemness of CSCs. Such lipogenesishi, SPDEFhi, and OPA1hi metabolic adaptions were verified with primary CSCs from lung cancer patients. Accordingly, blocking lipogenesis and mitochondrial fusion efficiently impeded CSC expansion and growth of organoids derived from patients with lung cancer. Together, lipogenesis regulates mitochondrial dynamics via OPA1 for controlling CSCs in human lung cancer.

Authors

Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen

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Figure 10

Patient-derived CSCs exert lipogenesishi, SPDEFhi, and OPA1hi.

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Patient-derived CSCs exert lipogenesishi, SPDEFhi, and OPA1hi. (A and B)...
(A and B) Patient-derived primary CD133+ and CD133– tumor cells were visualized for intercellular lipid deposition with confocal microscopy. Representative and mean ± SEM from 5 independent experiments. Nuclei were stained with DAPI. Scale bar: 5 μm. (C and D) Patient-derived primary CD133+ and CD133– tumor cells were analyzed for intracellular lipid accumulation using flow cytometry. Representative histograms and mean ± SEM from 6 independent experiments. (E and F) Patient-derived primary CD133+ and CD133– tumor cells were analyzed for intracellular SPDEF protein levels using flow cytometry. Representative and mean ± SEM from 6 independent experiments. (G and H) Patient-derived primary CD133+ and CD133– tumor cells were analyzed for intracellular OPA1 protein levels using flow cytometry. Shown from 5 independent experiments. Representatives from 6 independent experiments. Each dot represents data from 1 experiment. **P < 0.01, ***P < 0.001 with paired t test.