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. 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.
ER-positive (ER+) breast cancer, characterized by estrogen receptor expression on tumor cells, constitutes approximately 70% of all breast cancer cases. Identifying specific oncogenes and elucidating relevant oncogenic mechanisms are critical for developing effective therapies. ZNF703, a NET/N1Z family transcription factor, drives 8p12 locus amplification found in 10-20% of ER+ breast tumors. ZNF703 has been reported as an oncogene that promotes ER+ breast tumorigenesis in vitro. However, its regulation and in vivo oncogenic function remain unclear. We showed that ZNF703 expression is induced by estradiol in ER+ cell lines. ShRNA-mediated ZNF703 knockdown significantly reduced cell proliferation in MCF7 and BT474 cells. ZNF703 is post-translationally modified, which may affect its nuclear localization as well as its functions. Using mass spectrometry, we identified two asymmetrically di-methylated arginine residues (R544 and R580) on ZNF703 in human breast tumors. Protein arginine (R) methylation is catalyzed by protein arginine methyltransferases (PRMTs), which are classified into Type I, II, and III based on the type of methyl-R they produced. Among these, CARM1, a Type I PRMT, catalyzes asymmetric di-methylation of arginine residues. We showed that ZNF703 is methylated by CARM1 in in vitro methyltransferase assay. Furthermore, ZNF703 protein levels were reduced in CARM1 knockout MCF7 cells, accompanied by an increased degradation rate, suggesting that ZNF703 may be stabilized by CARM1. Given the lack of an ER+ breast cancer mouse model, we derived an ER+ MG1 rat cell line from estrogen-induced rat breast tumors. Consistent with our findings in human ER+ cell lines, ZNF703 was validated as an estrogen-induced gene in MG1 cells. ZNF703 knockout in MG1 cells impaired cell proliferation and colony formation. Functional rescue experiments demonstrated that re-expression of wild-type ZNF703 fully restored cell growth, whereas the methylation-deficient mutants ZNF703 R580K and R544K only partially rescued the proliferation defect. Our results implicate that CARM1-mediated ZNF703 methylation may regulate its stability and oncogenic functions. Given that patients diagnosed with 8p12 locus amplification caused by ZNF703 typically have poor prognosis, our MG-1/ACI rat syngeneic model would enable the investigation of ZNF703’s oncogenic functions in vivo. Jingjing Zhou, Eui-Jun Kim, Gui Ma, Ang Gao, Wei Xu. CARM1-mediated methylation of ZNF703 regulates its oncogenic functions in estrogen receptor positive breast cancer [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 4323.
Introduction and Objective: Population Achieved Sensitivity (PAS) assumes that the primary goal of a diagnostic process is to identify patients who can benefit from intervention. We used PAS to analyze adoption bias — characterized by inequitable adoption of AI technologies — for an autonomous AI for diabetic eye exams. Methods: We compared two autonomous AI algorithms paired with a desktop fundus camera and a handheld retina camera. Sensitivity for the preregistered clinical trials were reported (NCT02963441 and NCT05808699) and the PAS formula was derived from an ethical framework as presented in npj Digital Medicine - Nature. Access was estimated from the numbers of desktop fundus cameras and handheld retina cameras deployed in US primary care settings. The heatmap presents PAS values for any level of access (0-100% penetrance) and sensitivity ≥ 60%. Results: PAS increases with increasing access and/or sensitivity. The top-right quadrant shows the highest PAS value. Though the handheld retina camera has slightly lower sensitivity (82%) compared with the desktop fundus camera (87%), its greater potential for adoption (estimated at 10X) shows increased detection of diabetic retinal disease in real-world settings. Conclusion: Mitigating adoption bias requires balancing accuracy and access, quantifiable through PAS. This example illustrates how to achieve this balance, empowering clinicians to focus on both diagnostic accuracy and access. R. Channa: None. C. Joyce: Consultant; Digital Diagnostics. M.D. Abràmoff: Stock/Shareholder; Digital Diagnostics. Board Member; Digital Diagnostics. Consultant; Digital Diagnostics.
