Encapsulated multicellular breast cancer spheroids exhibit behavioural plasticity under non-negotiable mechanical stress

Abstract Cancerous growth, along with other known biological and biochemical signals, also depends on the biomechanical pressure wielded by the adjacent extracellular matrix (ECM). The dynamic relationship between the growing tumor and the ECM influences tumor growth, aggressiveness, and dormancy. Additionally, with time, the stroma also becomes subject to tumor-mediated remodeling through deformation and deposition cycles. In recent years, many studies have identified the dialog between the ECM and the tumor as one of the major causes behind increased metastasis and aggression. This study is designed to assess the impact of ECM-mediated mechanical stress on multicellular spheroids by encapsulating them within a non-proteinous matrix. The non-degradable nature of the matrix is instrumental in highlighting the impact of mechanical pressure on spheroid behavior, without accounting for tumor-mediated interference. Encapsulated spheroids exhibit restrained proliferation and increased cell death with increased stress. Compressive stress also contributes to sub-cellular re-organization and chemokine secretion. Transcriptomic analysis of the entrapped spheroids displays altered metabolism and protein trafficking while rearranging cell-cell and cell-substratum adhesion. Encapsulated spheroids remain static until they recognize neighboring micro-tracks within the matrix. Trapped spheroids perform non-adhesion-mediated collective migration within the microtracks. This behavior highlights the plasticity of the multicellular spheroids at the cellular level to survive the unfavorable conditions. This study would help identify mechanical stress-mediated pathways and catalog targets for therapeutic intervention.