Abstract LB083: Decoding systemic circadian regulation across multi-tissues in response to tumor stress

Abstract Emerging evidence suggests that tumors produce molecular signals to subvert and perturb circadian-regulated immune system functions. Elucidating the mechanisms of tumor-mediated circadian disruption will promote the development of new therapies targeting tumor remote regulatory abilities. Claudins, the structural backbone of tight junctions (TJs), play a pivotal role in tumor progression, metastasis, stemness, chemotherapy resistance, and crosstalk with signaling pathways in breast cancer, making them potential biomarkers for detection, diagnosis, and treatment. To explore how tumors remotely govern immune responses across tissues in a circadian manner in triple-negative breast cancer (TNBC), we generate a diurnal transcriptome in high (4T1) and low (E0771) claudin TNBC mouse models. We generated 528 transcriptomes from liver, spleen, thymus, bone marrow, PBMC, adjacent fat pad, distal fat pad, and control mammary fat pad, at four time points within a 24-hour cycle to understand tissue-wide and cell-type-specific responses to tumor stress. We found that tumor stress impacts gene expression across tissues. Key pathways are dysregulated in response to tumor stress irrespective of claudin levels, with upregulation in immune response and cell cycle regulation, and downregulation in metabolic pathways (DNA, lipid, monocarboxylic acid, and amino acid metabolism) across multiple tissues and tumor models. Rhythmicity analysis revealed that tumor stress-responsive tissues such as the spleen in 4T1 models and the thymus in E0771 models, exhibited shifts in circadian gene expression in tumor-bearing groups, with an increase in circadian-enhanced genes during the night. Our results suggest that tumor stress alters circadian gene regulation across tissues, triggering remote, cross-tissue interactions that disrupt tissue-specific functions in a coordinated, circadian-dependent manner. Citation Format: Chuqian Liang, Zunpeng Liu, Tao Zhang, Qi Zhang, Bingqiu Xiu, Gongwei Wu, Stuart Benjamin Fass, Li-Lun Ho, Manolis Kellis, Myles A. Brown. Decoding systemic circadian regulation across multi-tissues in response to tumor stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB083.