Proposed mechanisms underlying TMZ-mediated regulation of GCs migration. In GBM cells, WNK1 and OSR1 are the major kinases regulating NKCC1 activity under physiological condition and in the presence of TMZ treatment. WNK1/OSR1 kinases function in stimulation of NKCC1 activity to maintain K+i and Cl-i and cell volume homeostasis in the leading edge to promote cell migration. In addition, WNK1 may increase interactions between NKCC1 and ezrin to stimulate cell cytoskeletal rearrangements and further promote migration. Taken together, our findings suggest that targeting the WNK1/OSR1/NKCC1 pathway may synergistically reduce GBM cancer cell survival and migration in conjunction with TMZ treatment.