Abstract 1877: Decoding cancer prevention: Exercise, dark proteome signatures, and spatial proteomics

Abstract With rising cancer rates and widespread physical inactivity—a known risk factor for non-communicable diseases like cancer—exercise is increasingly recognized for its potential in cancer prevention and management. Despite strong evidence supporting its benefits, exercise remains underutilized in clinical oncology. Physical activity may reduce cancer risk and progression through mechanisms such as hormone regulation, reduced inflammation, improved insulin sensitivity, antioxidant enhancement, immune support, and direct tumor effects. Studies suggest that regular exercise could lower breast, colon, and lung cancer incidence by up to 40%. Exercise is generally safe for cancer patients, enhancing physical function, mental health, and potentially slowing tumor progression. Given that one-third of adults globally are inactive, incorporating exercise into cancer care offers a holistic approach to improve patient outcomes alongside conventional treatments. In our study, we used mass spectrometry-based serum proteomics to investigate exercise’s molecular effects on both the known and "Dark Matter" proteome—regions of proteins lacking structural characterization and potentially holding novel cancer biomarkers. We compared protein profiles between healthy individuals and pre-cancer patients, identifying early cancer signatures. Notably, Factor Xa (FA10), a vitamin K-dependent glycoprotein with pro-inflammatory effects, and fibulin-1 (FBLN1), a potential tumor suppressor involved in cell adhesion, were upregulated in pre-cancer patients. In an exercise intervention cohort, we observed that FA10 levels, initially elevated in pre-cancer patients, could be restored to baseline through exercise. This finding suggests that exercise may mitigate early cancer risk by reversing specific molecular changes associated with cancer progression. Ongoing work includes determining if unique proteins within the dark proteome can serve as distinctive cancer markers. We are currently performing spatial proteomics to determine the spatial distributions of selected dark proteome-derived proteins and to functionally characterize their roles in cancer prevention and progression. Citation Format: Parthiban Periasamy, Patrick Sitjar, Xinru Lim, Jiangfeng Ye, Meng Jia, Jorming Goh, Yap Yoon Sim, Darren Wan-Teck Lim Wan- Lim, Roger Ho, Joe Yeong. Decoding cancer prevention: Exercise, dark proteome signatures, and spatial proteomics [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 1877.