Abstract
SUMMARYMicrotubule-targeting agents (MTAs) are widely used chemotherapy drugs capable of disrupting microtubule-dependent cellular functions, such as division and migration. We show that two clinically approved MTAs, paclitaxel and vinblastine, each suppress stiffness-sensitive migration and polarization characteristic of human glioma cells on compliant hydrogels. MTAs influence microtubule dynamics and cell traction forces by nearly opposite mechanisms, the latter of which can be explained by a combination of changes in myosin motor and adhesion clutch number. Our results support a microtubule-dependent signaling-based model for controlling traction forces through a motor-clutch mechanism, rather than microtubules directly relieving tension within F-actin and adhesions. Computational simulations of cell migration suggest that increasing protrusion number also impairs stiffness-sensitive migration, consistent with experimental MTA effects. These results provide a theoretical basis for the role of microtubules and mechanisms of MTAs in controlling cell migration.
Highlights
Extensive and rapid tumor cell proliferation and tissue invasion are hallmarks of glioblastoma (GBM, grade IV glioma) and limit patient survival and treatment efficacy (Demuth and Berens, 2004; Lefranc et al, 2005)
We show that paclitaxel (PTX) and vinblastine (VBL), two clinically approved Microtubule-targeting agents (MTAs), impair stiffness-sensitive glioma migration, which they each accomplish by altering actin-based protrusion dynamics
Glioma cell migration is reportedly sensitive to nanomolar concentrations of various MTAs (Berges et al, 2014, 2016; Pagano et al, 2012; Panopoulos et al, 2011), so we sought to understand how MTAs influence microtubule dynamics in glioma cells
Summary
Extensive and rapid tumor cell proliferation and tissue invasion are hallmarks of glioblastoma (GBM, grade IV glioma) and limit patient survival and treatment efficacy (Demuth and Berens, 2004; Lefranc et al, 2005). Different MTA binding sites have distinct influences on microtubule polymer assembly: taxane site-binding MTAs promote assembly, whereas MTAs that bind the vinca or colchicine sites promote disassembly. While assembly promoters and disassembly promoters have divergent effects on polymer assembly, their common (convergent) phenotype is kinetic stabilization (Castle et al, 2017). It has long been assumed that MTAs block cell division to stall tumor spreading, but recent work found that MTA-induced mitotic arrest is dispensable for tumor regression (Zasadil et al, 2014). This contrasting finding raises the question: is the success of MTAs in cancer therapy due to blocking tumor cell invasion?
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