Abstract 305: Cellular senescence in human liver under normal aging and cancer

Abstract Liver senescence involves the gradual deterioration of hepatic cell function and reduction of regenerative capacity due to aging, chronic liver disease, and cancer. To elucidate the role of liver senescence in aging and cancer, we employed single-cell sequencing, spatial omics, and imaging approaches, collectively over 100 assays, to characterize 43 normal liver samples from a cohort of 95 donors, across ages and selected based on histology and clinical data. We conducted similar assays on samples from 24 patients with colorectal cancer metastasis in the liver. Our study identified CDKN1A+ senescent cells across four liver-resident cell types, namely hepatocytes, fibroblasts, cholangiocytes, and liver sinusoidal endothelial cells, with their prevalence significantly associated with age or liver disease. We observed distinct senescent populations in fibrotic compared to aged livers, indicating differential mechanisms of senescence in these conditions. Fibrosis was related to the expansion of a specific niche residing in portal triads and fibrous septae including immune cells and senescent fibroblasts, which exhibited abundant and strong cellular interactions. Notably, chemotherapy exacerbated senescence, increasing the number of senescent hepatocytes by five-fold compared to aging alone, while the effect of cancer itself was moderate. Other cell types affected by chemotherapy included liver sinusoidal endothelial cells and stellate cells, while CDKN1A+ portal fibroblasts and cholangiocytes were not affected as much. Cancer appeared to induce senescence in nearby hepatocytes, whereas chemotherapy severely affected more distant normal liver tissue. Cancer patients also demonstrated unique populations of CDKN2A+ hepatocytes and cholangiocytes with a distinct secretory phenotype. Senescent cells in liver shared core features, such as AP-1, NFkB activity, SERPINE1, CCL2, COL4A secretion, and anti-apoptotic protein expression, offering new insights into the cellular and molecular mechanisms underlying liver senescence. These findings underscore the complexity and heterogeneity of liver senescence and may have implications for our understanding of liver health and disease. Citation Format: Xiang Li, Alla Karpova, Chien-Wei Peng, Daniel R. Rapp, Kelsey L. Gallant, Andrew J. Houston, Andre Luiz N. Targino da Costa, Michael D. Iglesia, John M. Herndon, Kathleen Byrnes, Nataly Naser Al Deen, Wagma Caravan, Preet Lal, Reyka G. Jayasinghe, Jeffrey A. Blatnik, William G. Hawkins, Dominic E. Sanford, J. Chris Eagon, Natasha Leigh, Maria Bernadette M. Doyle, L. Michael Brunt, William C. Chapman, Roheena Z. Panni, Darren R. Cullinan, Sherri R. Davies, Matthew A. Wyczalkowski, Michael C. Wendl, Hong Zhang, Milan G. Chheda, Sheila A. Stewart, Feng Chen, Ryan C. Fields, Li Ding. Cellular senescence in human liver under normal aging and 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 305.