2. Academic Validation
  3. Intrinsic electrical activity drives small-cell lung cancer progression

Intrinsic electrical activity drives small-cell lung cancer progression

  • Nature. 2025 Feb 12. doi: 10.1038/s41586-024-08575-7.
Paola Peinado # 1,  Marco Stazi # 1,  Claudio Ballabio # 1,  Michael-Bogdan Margineanu 1,  Zhaoqi Li 2,  Caterina I Colón 2,  Min-Shu Hsieh 3,  Shreoshi Pal Choudhuri 4 5,  Victor Stastny 4 5,  Seth Hamilton 4 5,  Alix Le Marois 6,  Jodie Collingridge 7,  Linus Conrad 7,  Yinxing Chen 2,  Sheng Rong Ng 2,  Margaret Magendantz 2,  Arjun Bhutkar 2,  Jin-Shing Chen 8,  Erik Sahai 6,  Benjamin J Drapkin 4 5,  Tyler Jacks 2,  Matthew G Vander Heiden 2 9,  Maksym V Kopanitsa 1 10,  Hugh P C Robinson 1 7,  Leanne Li 11 12
Affiliations

Affiliations

  • 1 Cancer Neuroscience Laboratory, Francis Crick Institute, London, UK.
  • 2 Koch Institute of Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 3 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
  • 4 Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5 Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center, Dallas, TX, USA.
  • 6 Tumour Cell Biology Laboratory, Francis Crick Institute, London, UK.
  • 7 Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
  • 8 Division of Thoracic Surgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
  • 9 Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 Charles River Discovery Services, Portishead, UK.
  • 11 Cancer Neuroscience Laboratory, Francis Crick Institute, London, UK. leanne.li@crick.ac.uk.
  • 12 Koch Institute of Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. leanne.li@crick.ac.uk.
  • # Contributed equally.
PMID: 39939778 DOI: 10.1038/s41586-024-08575-7
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.

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