Intrinsic electrical activity drives small-cell lung cancer progression

• 成果类型: Article
• 署名作者: Peinado, Paola; Stazi, Marco; Ballabio, Claudio; Margineanu, Michael-Bogdan; Li, Zhaoqi; Colon, Caterina I.; Hsieh, Min-Shu; Pal Choudhuri, Shreoshi; Stastny, Victor; Hamilton, Seth; Le Marois, Alix; Collingridge, Jodie; Conrad, Linus; Chen, Yinxing; Ng, Sheng Rong; Magendantz, Margaret; Bhutkar, Arjun; Chen, Jin-Shing; Sahai, Erik; Drapkin, Benjamin J.; Jacks, Tyler; Vander Heiden, Matthew G.; Kopanitsa, Maksym V.; Robinson, Hugh P. C.; Li, Leanne
• 署名单位: Francis Crick Institute; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); National Taiwan University; National Taiwan University Hospital; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Francis Crick Institute; University of Cambridge; National Taiwan University; National Taiwan University Hospital; National Taiwan University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1630
• DOI: 10.1038/s41586-024-08575-7
• 发表日期: 2025-03-20
• 关键词: set enrichment analysis; mouse model; neuroendocrine cells; protein-kinase; growth-factor; c-fos; carcinoma; brain; phosphorylation; acetylcholine

摘要

Elevated or ectopic expression of neuronal receptors promotes tumour progression in many cancer types1,2; neuroendocrine (NE) transformation of adenocarcinomas has also been associated with increased aggressiveness3. Whether the defining neuronal feature, namely electrical excitability, exists in cancer cells and impacts cancer progression remains mostly unexplored. Small-cell lung cancer (SCLC) is an archetypal example of a highly aggressive NE cancer and comprises two major distinct subpopulations: NE cells and non-NE cells4,5. Here we show that NE cells, but not non-NE cells, are excitable, and their action potential firing directly promotes SCLC malignancy. However, the resultant high ATP demand leads to an unusual dependency on oxidative phosphorylation in NE cells. This finding contrasts with the properties of most cancer cells reported in the literature, which are non-excitable and rely heavily on aerobic glycolysis. Additionally, we found that non-NE cells metabolically support NE cells, a process akin to the astrocyte-neuron metabolite shuttle6. Finally, we observed drastic changes in the innervation landscape during SCLC progression, which coincided with increased intratumoural heterogeneity and elevated neuronal features in SCLC cells, suggesting an induction of a tumour-autonomous vicious cycle, driven by cancer cell-intrinsic electrical activity, which confers long-term tumorigenic capability and metastatic potential.