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J Cell Sci. 2019 Oct 10;132(19). pii: jcs228452. doi: 10.1242/jcs.228452.

Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells.

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School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
Leeds Institute for Data Analytics, University of Leeds, Leeds, LS2 9JT, UK.
School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
Department of Neurosurgery, Leeds General Infirmary, Leeds, LS1 3EX, UK.
Department of Biology, University of York, York, YO10 5DD, UK.
School of Medicine, University of Leeds, Leeds, LS2 9JT, UK


Tumor stem cells and malignant multicellular networks have been separately implicated in the therapeutic resistance of glioblastoma multiforme (GBM), the most aggressive type of brain cancer in adults. Here, we show that small-molecule inhibition of RHO-associated serine/threonine kinase proteins (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projections formed de novo-induced cellular network (iNet) 'webs', which regressed after withdrawal of ROCKi. Connected cells within the iNet web exhibited long range Ca2+ signal transmission, and significant lysosomal and mitochondrial trafficking. In contrast to their less-connected vehicle control counterparts, iNet cells remained viable and proliferative after high-dose radiation. These findings demonstrate a link between ROCKi-regulated cell projection dynamics and the formation of radiation-resistant multicellular networks. Our study identifies means to reversibly induce iNet webs ex vivo, and may thereby accelerate future studies into the biology of GBM cellular networks.


Brain tumor; GBM stem-like cells; Glioblastoma multiforme; Malignant multicellular network; Mitochondrial trafficking; Neurite-like outgrowth; Patient-derived tumor cells; ROCK inhibition; Radiation resistance


Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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