Abstract 6656: Cancer-derived polyamines regulate adipocyte lipolysis and fat waste in cancer cachexia

Abstract Cancer Cachexia (CC) accounts for more than 20% of all cancer-related deaths, rising to 30% in pancreatic cancer cases. Current treatments, which focus primarily on nutritional supplementation to address weight loss, are largely palliative and show limited efficacy. No pharmacologic therapy currently exists for CC. While skeletal muscle loss is a defining characteristic of cachexia, fat wasting often precedes muscle loss and is a stronger predictor of survival than overall body weight loss. Recognizing this, our study aims to identify cancer-secreted factors that drive adipocyte dysfunction and development of cachexia. To achieve this, we measured lipolytic activity in primary adipocytes exposed to conditioned media (CM) derived from various cancer cell lines. Remarkably, cancer cells from tumor types with a high incidence of cachexia, such as pancreatic ductal adenocarcinoma (PDAC) and head and neck cancers, induced significantly greater lipolysis compared to cells from cancers linked to lower cachexia incidence, such as breast cancer. Characterization of cancer-cell-secreted factors identified elevated polyamine levels in pro-cachectic CM. Consistently, we found that data from the Cancer Cell Line Encyclopedia also show an upregulation of the polyamine biosynthetic pathway in pro-cachectic cells. Using a syngeneic PDAC model, we observed that, in tumor-bearing mice, increased circulating lipids and fat loss correlated with elevated polyamine levels in the serum and the adipose tissue compared to sham controls. Mechanistically, high polyamine levels in cultured adipocytes and adipose tissue depots led to hyperhypusination of the eukaryotic translation initiation factor eIF5A. This unique post-translational modification activates eIF5A, enabling it to regulate protein translation, including key enzymes involved in lipolysis. Importantly, inhibiting either polyamine synthesis in cancer cells or eIF5A hypusination in adipocytes effectively blocked the pro-lipolytic effects of cancer cell CM, indicating that polyamines act as cancer-derived signaling molecules to promote lipid mobilization in adipocytes. This study sheds light on tumor-adipose tissue crosstalk and identifies cancer-derived polyamines as key drivers of cachexia. Specifically, polyamines promote the hyperhypusination of eIF5A, thereby enhancing lipolysis. These findings offer a foundation for developing anti-cachectic therapies targeting the polyamine-dependent hypusination of eIF5A. When combined with anti-cancer treatments, such therapies could significantly improve the quality of life and clinical outcomes for cancer patients suffering from cachexia. Citation Format: Matias Fabregat, Julia K. Hansen, Hoang V. Bui, Andrea Galmozzi. Cancer-derived polyamines regulate adipocyte lipolysis and fat waste in cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6656.