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 6

Lipogenesis drives OPA1 expression and mitochondrial fusion in CSCs.

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Lipogenesis drives OPA1 expression and mitochondrial fusion in CSCs. (A)...
(A) A549 tumor spheres were treated with the indicated doses of C75 for 12 hours and detected for OPA1 expression by qPCR. Mean ± SEM from 10 independent experiments. (B and C) A549 tumor spheres were treated with an increasing dose of C75 for 24 hours and detected for OPA1 protein with immunoblots. Representative and mean ± SEM from 5 independent experiments. (D) A549 tumor spheres were transfected with FASN siRNA or the control and detected for OPA1 expressions by qPCR after 12 hours. Mean ± SEM from 6 independent experiments. (E) A549 tumor spheres were transfected using a second FASN siRNA with or without the reintroduction of FASN by overexpression and were analyzed for OPA1 expression. Mean ± SEM from 8 independent experiments. (F and G) A549 tumor spheres with or without C75 treatment (50 μM) were detected for mitochondria morphology and areas. Scale bars: 500 nm. Representative and mean ± SEM from 5 independent experiments. Red arrows point to tubulated and elongated mitochondria. (H) A549 tumor spheres with or without C75 treatment (50 μM) were detected for mitochondrial OCR using Seahorse assay. Mean ± SEM from 5 independent experiments. **P < 0.01, ***P < 0.001 with ANOVA plus Tukey’s method (A–C and E) and paired t test (D and G).