Emma Ricci-De Lucca is majoring in Engineering and minoring in French at Swarthmore College. She is from the suburbs of Philadelphia as well as from Pisa, Italy. This summer, Emma is conducting research in Dr. Dennis Discher’s lab and exploring how cancer cells that undergo constricted migration in stiffer tissues experience nuclear envelope rupture and therefore DNA damage and genomic variation. Emma plans to pursue a graduate degree in biomedical engineering.
Hypotonic Versus Hypertonic Microenvironments Respectively Suppress or Enhance Nuclear Rupture During Cell Migration Through Micropores
During tumor growth and metastasis, cancer cells squeeze through interstitial pores, across basement membrane barriers, and into micron-sized blood capillaries. Along with these and other solid stresses, cancer cells also endure fluid stresses due to tumor microenvironments that can be dysregulated in terms of pH, osmolarity, and more. How osmolality influences a cancer cell’s migration through a constricting pore, or how the combination of constriction and osmotic stress impacts the integrity of the nucleus, are poorly understood issues. U2OS human osteosarcoma and A549 human lung cancer epithelial cells were seeded on a Transwell migration assay and the cells were incubated in hypoosmotic (~120 mOsm/kg), hyperosmotic (~650 mOsm/kg), or normal (~300 mOsm/kg) culture medium. After migration, the pore membranes were formaldehyde-fixed, stained for DNA, lamin-A/C, and lamin-B1, and imaged using a Leica TCS SP8 confocal microscope. For both cancer cell lines tested, hypoosmotic stress causes elevated cell death on a pore membrane—or possibly failure to adhere to the membrane—as well as reduced migration rate through both constricting 3 µm and larger 8 µm pores. Importantly, hypoosmotic stress also reduces the frequency of nuclear envelope rupture during constricted migration, as indicated by a ~25-30% decrease in nuclear bleb formation. Tumor growth and metastasis depend on cell migration, and cancer cells that squeeze through stiffer tissues—and therefore smaller interstitial pores—experience greater mechanical stress, which can also be induced by varying the osmolalities of the solutions in which cells migrate. Cytoskeletal organization might be altered and could provide insight into these differential effects.