Intrinsic electrical activity drives small-cell lung cancer progression

Paola Peinado, Marco Stazi, Claudio Ballabio, Michael-Bogdan Margineanu, Zhaoqi Li, Caterina I. Colón, Min-Shu Hsieh, Shreoshi Pal Choudhuri, Victor Stastny, Seth Hamilton, Alix Le Marois, Jodie Collingridge, Linus Conrad, Yinxing Chen, Sheng Rong Ng, Margaret Magendantz, Arjun Bhutkar, Jin-Shing Chen, Erik Sahai, Benjamin J. Drapkin, Tyler Jacks, Matthew G. Vander Heiden, Maksym V. Kopanitsa, Hugh P. C. Robinson and Leanne Li ()
Additional contact information
Paola Peinado: Francis Crick Institute
Marco Stazi: Francis Crick Institute
Claudio Ballabio: Francis Crick Institute
Michael-Bogdan Margineanu: Francis Crick Institute
Zhaoqi Li: Massachusetts Institute of Technology
Caterina I. Colón: Massachusetts Institute of Technology
Min-Shu Hsieh: National Taiwan University Hospital
Shreoshi Pal Choudhuri: University of Texas Southwestern Medical Center
Victor Stastny: University of Texas Southwestern Medical Center
Seth Hamilton: University of Texas Southwestern Medical Center
Alix Le Marois: Francis Crick Institute
Jodie Collingridge: University of Cambridge
Linus Conrad: University of Cambridge
Yinxing Chen: Massachusetts Institute of Technology
Sheng Rong Ng: Massachusetts Institute of Technology
Margaret Magendantz: Massachusetts Institute of Technology
Arjun Bhutkar: Massachusetts Institute of Technology
Jin-Shing Chen: National Taiwan University Hospital and National Taiwan University College of Medicine
Erik Sahai: Francis Crick Institute
Benjamin J. Drapkin: University of Texas Southwestern Medical Center
Tyler Jacks: Massachusetts Institute of Technology
Matthew G. Vander Heiden: Massachusetts Institute of Technology
Maksym V. Kopanitsa: Francis Crick Institute
Hugh P. C. Robinson: Francis Crick Institute
Leanne Li: Francis Crick Institute

Nature, 2025, vol. 639, issue 8055, 765-775

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08575-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:639:y:2025:i:8055:d:10.1038_s41586-024-08575-7

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08575-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().