Drug Resistance in Glioma Cells Induced by a Mesenchymal–Amoeboid Migratory Switch

Abstract

Cancer cell invasion is a precondition for tumour metastasis and represents one of the most devastating characteristics of cancer. The development of drugs targeting cell migration, known as migrastatics, may improve the treatment of highly invasive tumours such as glioblastoma (GBM). In this study, investigations into the role of the cell adhesion protein Cellular communication network factor 1 (CCN1, also known as CYR61) in GBM cell migration uncovered a drug resistance mechanism adopted by cells when treated with the small molecule inhibitor CCG-1423. This inhibitor binds to importin α/β inhibiting the nuclear translocation of the transcriptional co-activator MKL1, thus preventing downstream effects including migration. Despite this reported role as an inhibitor of cell migration, we found that CCG-1423 treatment did not inhibit GBM cell migration. However, we could observe cells now migrating by mesenchymal–amoeboid transition (MAT). Furthermore, we present evidence that CCN1 plays a critical role in the progression of GBM with increased expression in higher-grade tumours and matched blood samples. These findings support a potential role for CCN1 as a biomarker for the monitoring and potentially early prediction of GBM recurrence, therefore as such could help to improve treatment of and increase survival rates of this devastating disease.

Traditional Plant-Derived Compounds Inhibit Cell Migration and Induce Novel Cytoskeletal Effects in Glioblastoma Cells

“…The visualization of the spheroids and migratory cells in their collagen plugs via confocal microscopy supports our suggestion of a morphological transition to amoeboid cell morphology and cell migration/invasion induced by Turmeric, compared to the elongated cell bodies observed in cells emanating from the control, mock-treated spheroids, although this effect was not observed at the lower concentration. In addition, we suggest a possible switch to collective cell migration in response to Turmeric, which has been noted in established glioma cell lines following anti-migratory drug treatment [ 34 ].…”

Inference of glioblastoma migration and proliferation rates using single time-point images

“…We failed to acquire one drug, pitavastatin and used simvastatin as a replacement instead. Two GSK3-inhibitors; an indirubin derivative (7BIO), AZD2858, as well as the RhoA inhibitor CCG-1424, previously implicated to have anti-migratory effects in GBM [27][28][29] , were also added to the panel. Cells were imaged every 30 min, tracked, and treated at 11 different concentrations, with two replicates at each concentration.…”

“…These compounds included two GSK3 inhibitors (indirubin and AZD2858) and a RhoA inhibitor (CCG-1423). Previous data for these compounds, collected across a limited number of doses and GBM cell lines indicate effects on cell migration [27][28][29] . Of note, CCG-1423 can induce a mesenchymal-amoeboid switch in 3D cultures 27 .…”

“…Previous data for these compounds, collected across a limited number of doses and GBM cell lines indicate effects on cell migration [27][28][29] . Of note, CCG-1423 can induce a mesenchymal-amoeboid switch in 3D cultures 27 . Further work will be needed to fully explain the differences between individual patient-derived cell cultures, and evaluate effects in 3D assays, reserved for future work.…”

Novel Anti-Cancer Agents and Cellular Targets and Their Mechanism(s) of Action

“…This has stimulated interest in pharmacological inhibition of cell migration as part of the regime for treating glioblastomas. Ketchen et al report on the migratory plasticity of GBM cells and how the pharmacological inhibition of mesenchymal migration, via the inhibition of cellular communication network factor 1 (CCN1), promotes cells to ‘switch’ to an alternative means of migration known as ameboid migration [ 3 ]. This work indicates the importance of simultaneously targeting multiple alternative modes of GBM cell migration.…”