美国麻省理工学院Leanne Li研究小组近日取得一项新成果。经过不懈努力，他们提出了内在电活动驱动小细胞肺癌的进展。这一研究成果于2025年2月12日发表在国际顶尖学术期刊《自然》上。

本研究表明，NE细胞是可兴奋的，而非NE细胞是可兴奋的，它们的动作电位放电直接促进SCLC恶性肿瘤。

然而，由此产生的高ATP需求导致NE细胞对氧化磷酸化的非特异性依赖。这一发现与文献中报道的大多数癌细胞的特性形成对比，这些癌细胞是不可兴奋的，并且严重依赖于有氧糖酵解。此外，课题组研究人员发现非NE细胞在代谢上支持NE细胞，这一过程类似于星形胶质细胞-神经元代谢物穿梭。最后，该课题组观察到SCLC进展过程中神经支配景观的剧烈变化，这与SCLC细胞内异质性的增加和神经元特征的升高相吻合，表明肿瘤-自主细胞恶性循环的诱导，由癌细胞固有的电活动驱动，这赋予了长期的致瘤能力和转移潜力。

据介绍，在许多癌症类型中，神经元受体的升高或异位表达促进肿瘤的进展；腺癌的神经内分泌（NE）转化也与侵袭性增加有关。是否定义神经元特征，即电兴奋性，存在于癌细胞中并影响癌症进展仍未被探索。小细胞肺癌（SCLC）是高度侵袭性NE癌的典型例子，包括两个主要的不同亚群：NE细胞和非NE细胞。

附：英文原文

Title: Intrinsic electrical activity drives small-cell lung cancer progression

Author: Peinado, Paola, Stazi, Marco, Ballabio, Claudio, Margineanu, Michael-Bogdan, Li, Zhaoqi, Coln, 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

Issue&Volume: 2025-02-12

Abstract: 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.

DOI: 10.1038/s41586-024-08575-7

Source: https://www.nature.com/articles/s41586-024-08575-7