Differential biophysical mechanisms driving cancer stem cell migration
2022-01
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Differential biophysical mechanisms driving cancer stem cell migration
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2022-01
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Cancer stem cells (CSCs) are known to have a high capacity for tumor initiation and are likely a key player in the formation of metastases. We have previously shown that in aligned collagen constructs similar to in vivo structures indicative of disease progression, breast CSCs demonstrate enhanced directional and total motility compared to the carcinoma population as a whole (WP). Here, we show that increased motility is maintained by CSCs in diverse environments including elastic, nonaligned 2D polyacrylamide gels at various stiffness; 3D randomly oriented collagen matrices; and ectopic cerebral slices representative of common metastatic sites. The consistency of CSCs’ enhanced motility across diverse environments suggests a general shift in cell migration mechanics between well differentiated carcinoma cells and their stem-like counterparts. To further elucidate the source of differences in migration, we demonstrate that CSCs are less contractile than the carcinoma population as a whole and concomitantly produce fewer and smaller focal adhesions. This shift in CSC biophysical behavior can be tuned via contractility. The WP can be shifted to a CSC-like enhanced migratory phenotype using partial myosin II inhibition. Inversely, CSCs can be shifted to a less migratory WP-like phenotype using microtubule destabilizing drugs to increase contractility. This work begins to elucidate the mechanistic differences driving CSC migration and raises important implications regarding the potentially disparate effects of microtubule-targeting agents on the motility of different cell populations.
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University of Minnesota Ph.D. dissertation. January 2021. Major: Biomedical Engineering. Advisor: Paolo Provenzano. 1 computer file (PDF); xi, 94 pages + 1 compressed folder of supplementary videos.
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Heussner, Rachel. (2022). Differential biophysical mechanisms driving cancer stem cell migration. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/253423.
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