Intrinsic electrical activity drives small-cell lung cancer progression
Journal
Nature
ISSN
0028-0836
1476-4687
Date Issued
2025-02-12
Author(s)
Paola Peinado
Marco Stazi
Claudio Ballabio
Michael-Bogdan Margineanu
Zhaoqi Li
Caterina I. Colón
Shreoshi Pal Choudhuri
Victor Stastny
Seth Hamilton
Alix Le Marois
Jodie Collingridge
Linus Conrad
Yinxing Chen
Sheng Rong Ng
Margaret Magendantz
Arjun Bhutkar
Erik Sahai
Benjamin J. Drapkin
Tyler Jacks
Matthew G. Vander Heiden
Maksym V. Kopanitsa
Hugh P. C. Robinson
Leanne Li
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.
Publisher
Springer Science and Business Media LLC
Type
journal article