title: Osmotic Regulation Is Required for Cancer Cell Survival under Solid Stress.
abstract: For a solid tumor to grow, it must be able to support the compressive stress that is generated as it presses against the surrounding tissue. Although the literature suggests a role for the cytoskeleton in counteracting these stresses, there has been no systematic evaluation of which filaments are responsible or to what degree. Here, using a three-dimensional spheroid model, we show that cytoskeletal filaments do not actively support compressive loads in breast, ovarian, and prostate cancer. However, modulation of tonicity can induce alterations in spheroid size. We find that under compression, tumor cells actively efflux sodium to decrease their intracellular tonicity, and that this is reversible by blockade of sodium channel NHE1. Moreover, although polymerized actin does not actively support the compressive load, it is required for sodium efflux. Compression-induced cell death is increased by both sodium blockade and actin depolymerization, whereas increased actin polymerization offers protective effects and increases sodium efflux. Taken together, these results demonstrate that cancer cells modulate their tonicity to survive under compressive solid stress.
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McGrail
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: McAndrews
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Chandler P
authors.initials: CP
authors.lastname: Brandenburg
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Nithin
authors.initials: N
authors.lastname: Ravikumar
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Quang Minh N
authors.initials: QM
authors.lastname: Kieu
authors.affiliation: School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia; The Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia. Electronic address: mdawson@gatech.edu.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Dawson
mesh_terms: D000199:Actins / Q000378:metabolism; D000230:Adenocarcinoma / Q000503:physiopathology*; D001386:Azides; D001696:Biomechanical Phenomena; D001943:Breast Neoplasms / Q000503:physiopathology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives; D006801:Humans; D008954:Models, Biological; D009995:Osmosis / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism; D054457:Tissue Scaffolds
chemical_list: D000199:Actins; D001386:Azides; D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C031907:GTP gamma-4-azidoanilide; D006160:Guanosine Triphosphate; D012964:Sodium