Journal Article Epublish
PubMed: 40595538 DOI: 10.1038/s41467-025-60730-4
Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI.
Nat Commun 16(1):5608
Authors: Abhishek Tyagi, Shih-Ying Wu, Jee-Won Kim, Ravindra Pramod Deshpande, Kerui Wu, Eleanor C Smith, Giuseppe L Banna, Kounosuke Watabe
Affiliations
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
- Nanoscience Department, Joint School of Nanoscience & Nanoengineering, Greensboro, NC, 27401, USA.
- Portsmouth Hospitals University NHS Trust, Faculty of Science and Health, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
Abstract
Obesity is a known risk factor for many cancers, yet recent studies reveal a paradoxical association between low body mass index (BMI) and increased brain metastasis in lung cancer-referred to as the "obesity paradox," with unclear molecular mechanism(s). Here, we show a significantly higher incidence of brain metastasis in low-BMI lung cancer patients compared to those with high-BMI or other cancer brain metastasis in a pan-analysis of 7628 patients. Mechanistically, low BMI activates ghrelin-GHSR signaling, increasing neuronal neuropeptide Y (NPY) secretion, which promotes tumor metabolic reprogramming via NPY-Y5R, facilitating brain colonization. Elevated plasma ghrelin levels in cancer-free low-BMI subjects suggest its potential as a prognostic biomarker for predicting brain metastasis. Notably, targeting NPY-Y5R or reversing low BMI effectively suppresses brain metastasis, supporting its pro-metastatic role. These findings provide a strong rationale for developing targeted interventions to treat or prevent brain metastasis in lung cancer patients with low BMI.
MeSH
Lung, Brain, Neoplasms, Lung Neoplasms, Neoplasm Metastasis, Ghrelin