The effects of mechanical confinement on cancer cell growth and migration mechanisms

Cancer is a disease in which cell growth proceeds unchecked and cells accumulate mutations to adopt an invasive and migratory phenotype that promotes metastasis. Once a cancer becomes metastatic, survival rates plummet, and vast tumor heterogony and lesion formation leave current therapeutics and treatments unable to maintain pace. Therefore, there exists a clinical need to gain a more complex understanding of factors that promote and encourage metastasis. Cancer cells are subjected to mechanical forces in vivo that influence their behavior. Mechanical cues are transmitted through the cell from the membrane to the cytoskeleton, and ultimately to the nucleus where gene expression and subsequently protein output can be altered. In this dissertation, we probed the effects of mechanical confinement, a restrictive force present at various stages during the metastatic cascade, on (1) cancer cell growth and cell cycle progression, (2) global mRNA translational and its relationship to cell migration, and (3) mRNA localization mechanisms for use in confined cell migration. We modeled confinement in vitro through fabrication of microfluidic microchannel devices. We show here that mechanical confinement halts sarcoma cell cycle progression and division and leads to an increase in abnormal divisions. We explored the connection between mRNA translation and cell migration and found that global mRNA translation is spatially altered in confinement and that it is necessary for confined cell migration. We explored this idea further, investigating a subset of mRNAs that are known to influence cell migration in unconfined spaces and show that their regulation in confinement is cell type dependent, but that it primarily relies on cell mechanoactivity. Together, this work contributes a detailed understanding of key cell behaviors that are altered in confined environments and emphasizes the importance of studying mechanical cues that cells experience in vivo, in the context of understanding and treating cancer progression and metastasis