Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC

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.

Automated summary

Cancer stem-like cells (CSCs) play a critical role in cancer metastasis and chemoresistance, posing a major challenge in clinical practice. In this study, it was found that human lung CSCs exhibit metabolic reprogramming characterized by enhanced lipogenesis and mitochondrial fusion regulated by OPA1. Transcription factor SPDEF induces OPA1 expression, promoting mitochondrial fusion and the stemness of CSCs. Blocking lipogenesis and mitochondrial fusion can effectively inhibit the growth and expansion of CSCs in lung cancer patients.