Chemically-induced Neurite-like Outgrowth Reveals Multicellular Network Function in Patient-derived Glioblastoma Cells

TY - JOUR

T1 - Chemically-induced Neurite-like Outgrowth Reveals Multicellular Network Function in Patient-derived Glioblastoma Cells

AU - da Silva, Barbara

AU - Irving, Bronwyn K.

AU - Polson, Euan S.

AU - Droop, Alastair

AU - Griffiths, Hollie B.S.

AU - Mathew, Ryan K.

AU - Stead, Lucy F.

AU - Marrison, Joanne

AU - Williams, Courtney

AU - Williams, Jennifer

AU - Short, Susan C.

AU - Scarcia, Margherita

AU - O'Toole, Peter John

AU - Allison, Simon J.

AU - Mavria, Georgia

AU - Wurdak, Heiko

N1 - © 2019. Published by The Company of Biologists Ltd. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

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. We show that small molecule inhibition of RHO-associated serine/threonine kinase (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projectionsformed de novo -induced cellular network (iNet) ‘webs’, which regressed after withdrawal of ROCKi. Connected cells within the iNet web exhibited long range calcium 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. We show that small molecule inhibition of RHO-associated serine/threonine kinase (ROCKi) significantly promoted the outgrowth of neurite-like cell projections in cultures of heterogeneous patient-derived GBM stem-like cells. These projectionsformed de novo -induced cellular network (iNet) ‘webs’, which regressed after withdrawal of ROCKi. Connected cells within the iNet web exhibited long range calcium 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.

U2 - 10.1242/jcs.228452

DO - 10.1242/jcs.228452

M3 - Article

SN - 0021-9533

VL - 132

JO - Journal of Cell Science

JF - Journal of Cell Science

M1 - jcs228452

ER -