Abstract 5515: Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung cancer

Abstract

Abstract Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To develop a more effective therapeutic strategy, it is crucial to understand the underlying pathological mechanism of brain metastasis. Recent clinical data has unveiled a significant association between low body mass index (BMI) and an increased risk of brain metastasis in lung cancer patients, leading to reduced survival rates compared to other primary tumors. However, the molecular mechanism underlying this paradoxical relationship, often referred to as the "obesity paradox," in the context of lung cancer mortality presents a complex and intriguing puzzle and warrants in-depth investigation. Here, we examined biological mechanism of how low BMI promotes lung cancer brain metastasis. In this study, we conducted a retrospective pan-analysis of 5,516 patient cohorts with brain metastasis originating from lung, breast, melanoma, and renal cancers with their BMI status. We found that lung cancer patients with low BMI have significantly higher brain metastatic incidence compared to the high BMI patients, in contrast to breast, melanoma, and renal cancers. Furthermore, we found that low BMI plays a pivotal role in mediating neuron activation within the brain and that the secretion of neuronal neuropeptide Y (NPY), a protein involved in appetite and energy homeostasis via GHSR-receptor manner, promotes metabolic switching through NPY/NPY5R axis in the tumor cells in the brain thereby enabling metastasis. Elevated levels of neuronal NPY in the brains of cancer-free subjects with low BMI suggest its potential utility as a promising prognostic biomarker for identifying the increased risk of metastatic disease in lung cancer patients with low BMI. We also demonstrated that reversing low BMI or blocking the NPY/Y5R interactions effectively abrogated brain metastasis in our animal model. Our findings suggest a novel pro-metastatic role of low BMI-induced NPY in the progression of brain metastasis. We emphasize the importance of elucidating the clinical implications of this relationship to develop an updated intervention strategy for the clinical care of patients with lung cancer and low BMI. Citation Format: Abhishek Tyagi, Shih-Ying Wu, Ravindra Deshpande, Kerui Wu, Liang Liu, Kounosuke Watabe. Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5515.