The effects of incremental solid stress compression on mechano-sensitive targets and its role in breast cancer malignancy

• Main Author: Muhammad Farouq Bin Azizan
• Other Authors: Koh Cheng Gee
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Medicine, Health and Life Sciences; Solid stress; Breast cancer
• Online Access: https://hdl.handle.net/10356/175756
• Institution: Nanyang Technological University

As a tumour mass rapidly expands and pushes on the surrounding host tissues within a finite space, an equal and externally applied force known as solid stress is returned on the tumour mass. Studies have found that solid stress compression induces molecular signalling cascades such as the Akt-GSK-3β-β-catenin pathway, genotypic and phenotypic changes within cancer cells that favour an invasive and metastatic phenotype. The effects of solid stress compression, on the mechanotransduction of Akt signalling cascade and global transcriptomic alterations, especially in breast cancer cells, remains limited. To mimic the varying solid stress pressures experienced by peripheral cancer cells during tumour progression, this study utilised a 2D in vitro compression setup to apply three incremental solid stress compression: 386.5 Pascal (Pa), 773.0 Pa, the estimated breast tumour microenvironment pressure and 1546.0 Pa. This study has found that breast cancer cells under incremental solid stress exhibited cellular migration that follows a biphasic curve where migratory capacity is elevated under 386.5 Pa, the highest under 773.0 Pa of solid stress and reduced under 1546.0 Pa. Global transcriptome analysis found the upregulation of many genes including a vital cytokine in breast cancer progression and metastasis, Interleukin 6 (IL-6). Western blot analysis found that solid stress upregulated both the protein levels of IL-6 and SNAI1 and secretion of IL-6 cytokines in a biphasic manner. In contrast, the main transducer of IL-6 signaling, STAT3, showed elevated phosphorylation status in a stepwise manner with increasing solid stress. Knockdown of IL-6 significantly reduced cell migration in compressed breast cancer cells suggesting that IL6 might play a role in the solid stress- induced cancer cell migration. Furthermore, the elevated SNAI1 protein levels were dependent on the elevated IL-6 levels induced by solid stress. 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. For the first time, this study links solid stress compression, a biomechanical cue prevalent in solid tumours, to the upregulation of Interleukin-6, a pivotal regulator in cancer progression.