Preventing cellular interactions as novel treatment strategy

Cancer cells are dependent on interactions with their solid microenvironment for both survival, particularly after being challenged by (chemo)therapy, and motility, the latter being a prerequisite for invasion and, thus, metastasis. Using Glioblastoma, an exceptionally invasive brain tumour that exhibits a high degree of resistance towards treatment-induced apoptosis, as a model we identified two promising substances, Carbenoxolone and Disulfiram, that inhibit disparate forms of cellular interactions – gap junctions and focal adhesions, respectively. We could show further that distinct patient-derived cell populations originating from a single donor exhibit different sensitivities towards the substances: stem cell-like cells cultured as neurospheres are more sensitive towards Carbenoxolone, while adherent cells respond more strongly to Disulfiram. Importantly, the combination of both substances is necessary to achieve a significantly reduction in tumour motility, while concurrently inducing spontaneous cell death, i.e. anoikis. We therefore propose the use of both substances, which have a long established history of use in the clinic, as part of a multi-targeted approach that aims to prevent cellular interactions of cancer cells with their solid microenvironment – 'normal' cells, other cancer cells or the extracellular matrix – without increasing their potential to invade, i.e. without triggering epithilial-to-mesenchymal transition.

^*contributed equally