Abstract While tumour cells are known to respond to biochemical signals, the influence of physical and mechanical cues is increasingly more recognised. Solid stress arises from tumour expansion, where growing tumour masses and surrounding tissue exert equal and opposite forces on each other. This biomechanical force has been associated with increased metastatic behaviour in various cancers. In this study, we investigated the effects of solid stress compression on breast cancer cells. We applied solid stress compression on MDA-MB-231 breast cancer cells using a 2D in-vitro compression setup. Three incremental solid stress compressions were applied: 386. 5 Pascal (Pa), 773. 0 Pa (the estimated breast tumour microenvironment pressure), and 1546. 0 Pa, mimicking the pressures experienced by cells at the periphery of the tumour mass. After 16 hours of compression, the cells were harvested for RNA-sequencing, western blotting, and migration assays. Our findings revealed that compression enhanced migration in MDA-MB-231 cells in a biphasic manner. Migration peaked at 773. 0 Pa and declined slightly at 1546. 0 Pa but remained above control levels. Global transcriptome analysis revealed upregulation of many genes, including Interleukin-6 (IL-6), a vital cytokine in breast cancer progression. Western blotting demonstrated that solid stress upregulated protein levels of IL-6 and SNAI1, as well as IL-6 secretion. STAT3, the main transducer of IL-6 signalling, also showed elevated phosphorylation status with increasing solid stress. Our data suggest solid stress compression leads to the activation of the IL-6/IL-6R/STAT3 signalling pathway. This study links solid stress compression to the upregulation of IL-6. In the context of breast cancer, solid stress appears to elicit a more aggressive phenotype through the upregulation of genes such as IL-6 and SNAI1. Solid stress compression also leads to increased secretion of IL-6, which might act in autocrine and paracrine manners to activate IL-6 signalling and upregulate downstream gene targets such as SNAI1. Citation Format: Ryna Shireen Sheriff, Farouq Azizan, Koh Cheng Gee. SOLID STRESS ACTIVATED IL-6/JAK/STAT3 PATHWAY TO INCREASE BREAST CANCER CELL MIGRATION AND INVASION abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P97.
Sheriff et al. (Thu,) studied this question.