Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis

Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms<sup>1</sup> and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses<sup>2,3</sup>. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression<sup>4-12</sup>. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron-cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis.

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Publication Details

Journal
Nature
Published
2025-09-10
DOI
https://doi.org/10.1038/s41586-025-09492-z
Citations
26
Primary Topic
Lung Cancer Research Studies
Type
article
Field-Weighted Citation Impact
27.18
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article

Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis

Mariella G. Filbin, Lijun Ni, Lehi Acosta-Alvarez, Belgin Yalçın et al.
26 citations
Nature
Lung Cancer Research Studies
27.18
article

Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis

Mariella G. Filbin, Lijun Ni, Lehi Acosta-Alvarez, Belgin Yalçın, Keith Lloyd Ligon, Humsa S. Venkatesh, Elana Carleton, Michelle Monje, Wengang Wang, Pamelyn J. Woo, Mark A. Krasnow, Fangfei Qu, Yin Liu, Johannes C. Melms, Bernardo L. Sabatini, Angus Toland, Jenna LaBelle, Carlos Alberto Oliveira de Biagi, Benjamin Izar, Solomiia Savchuk, Karan Luthria, Griffin G. Hartmann, Julien Sage, Richard Drexler, Elisa C. Pavarino, Kaylee M. Gentry, Hannah C Farnsworth, Rachel A. Davis, Yoon Seok Kim
article en
26 citations

Abstract

Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms<sup>1</sup> and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses<sup>2,3</sup>. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression<sup>4-12</sup>. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron-cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis.

NatureVol. 646(8087)
Brigham and Women's Hospital (US), Howard Hughes Medical Institute (US), Harvard University (US), Columbia University Irving Medical Center (US), Dana-Farber Cancer Institute (US), Stanford Medicine (US), Pediatrics and Genetics (US), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), Stanford University (US)
Openalex Percentile: Top 0%
Lung Cancer Research Studies
27.18
DOIOpen Access PDFOpenAlex
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