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

Bárbara da Silva, Bronwyn Irving, Euan S Polson, Alastair Droop, Hollie Griffiths, Ryan K Mathew, Lucy Stead, Joanne Marrison, Courtney Williams, Jennifer Williams, Susan C Short, Margherita Scarcia, Peter O'Toole, Simon J. Allison, Georgia Mavria, Heiko Wurdak

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalJournal of Cell Science
Volume132
Issue number19
Early online date12 Sep 2019
DOIs
Publication statusPublished - 10 Oct 2019

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Glioblastoma
Radiation
Neoplastic Stem Cells
Protein-Serine-Threonine Kinases
Brain Neoplasms
Stem Cells
Neuronal Outgrowth
Therapeutics

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da Silva, B., Irving, B., Polson, E. S., Droop, A., Griffiths, H., Mathew, R. K., ... Wurdak, H. (2019). Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells. Journal of Cell Science, 132(19). https://doi.org/10.1242/jcs.228452
da Silva, Bárbara ; Irving, Bronwyn ; Polson, Euan S ; Droop, Alastair ; Griffiths, Hollie ; Mathew, Ryan K ; Stead, Lucy ; Marrison, Joanne ; Williams, Courtney ; Williams, Jennifer ; Short, Susan C ; Scarcia, Margherita ; O'Toole, Peter ; Allison, Simon J. ; Mavria, Georgia ; Wurdak, Heiko. / Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells. In: Journal of Cell Science. 2019 ; Vol. 132, No. 19.
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abstract = "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.",
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da Silva, B, Irving, B, Polson, ES, Droop, A, Griffiths, H, Mathew, RK, Stead, L, Marrison, J, Williams, C, Williams, J, Short, SC, Scarcia, M, O'Toole, P, Allison, SJ, Mavria, G & Wurdak, H 2019, 'Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells', Journal of Cell Science, vol. 132, no. 19. https://doi.org/10.1242/jcs.228452

Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells. / da Silva, Bárbara; Irving, Bronwyn; Polson, Euan S; Droop, Alastair; Griffiths, Hollie; Mathew, Ryan K; Stead, Lucy; Marrison, Joanne; Williams, Courtney; Williams, Jennifer; Short, Susan C; Scarcia, Margherita; O'Toole, Peter; Allison, Simon J.; Mavria, Georgia; Wurdak, Heiko.

In: Journal of Cell Science, Vol. 132, No. 19, 10.10.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chemically induced neurite-like outgrowth reveals a multicellular network function in patient-derived glioblastoma cells

AU - da Silva, Bárbara

AU - Irving, Bronwyn

AU - Polson, Euan S

AU - Droop, Alastair

AU - Griffiths, Hollie

AU - Mathew, Ryan K

AU - Stead, Lucy

AU - Marrison, Joanne

AU - Williams, Courtney

AU - Williams, Jennifer

AU - Short, Susan C

AU - Scarcia, Margherita

AU - O'Toole, Peter

AU - Allison, Simon J.

AU - Mavria, Georgia

AU - Wurdak, Heiko

PY - 2019/10/10

Y1 - 2019/10/10

N2 - 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.

AB - 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.

KW - Brain tumor

KW - GBM stem-like cells

KW - Glioblastoma multiforme

KW - Malignant multicellular network

KW - Mitochondrial trafficking

KW - Neurite-like outgrowth

KW - Patient-derived tumor cells

KW - Radiation resistance

KW - ROCK inhibition

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U2 - 10.1242/jcs.228452

DO - 10.1242/jcs.228452

M3 - Article

VL - 132

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

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