Irradiation of glioblastoma cells can promote enhanced motility and invasiveness, both in vitro and in vivo through activation of MRCK

Glioblastoma (GBM) is one of the most common and aggressive forms of brain cancer. It is associated with poor survival rates, in part due to the infiltrative nature of GBM tumour cells. This allows GBM cells to disseminate... [ view full abstract ]

Glioblastoma (GBM) is one of the most common and aggressive forms of brain cancer. It is associated with poor survival rates, in part due to the infiltrative nature of GBM tumour cells. This allows GBM cells to disseminate through the brain via existing white matter tracts and perivascular spaces making complete surgical resection unachievable and contributing to high recurrence rates. For the majority of patients treatment of GBM includes radiotherapy. However, radiation resistance results in populations of surviving tumour cells with the potential for modified behaviour through radiation-induced alterations in signalling and gene expression profiles

Myotonic dystrophy kinase-related CDC42- binding kinase (MRCK) is involved in regulating actin-myosin dynamics during cell migration through phosphorylation of its targets MLC2 and MYPT. Upon radiation of GBM cell lines in vivo we observed an increase in MRCK activity which was concomitant with a significant increase in GBM cell motility and invasion in in vitro and ex vivo assays. In support of these data we have observed increased MRCK activity at the invasive edges of both clinical GBM samples and an orthotopic GBM xenograft model that recapitulates key histological features of human GBM. Furthermore, therapeutic doses of irradiation were found to promote GBM invasion in vivo in this xenograft model, along with increased pMYPT. These observations suggest that MRCK activity may be required to promote invasion following irradiation and therefore may present a promising novel target for GBM treatment.

In support of this, we found we were able to reverse the radiation dependent promotion of GBM cell motility via MRCK RNAi or by using a novel MRCK selective inhibitor, BDP-9066. These data suggest that MRCK activity is indeed required for GBM invasion and may offer a potential new target for GBM management.