Microtubule-Based Control of Motor-Clutch System Mechanics in Glioma Cell Migration

Louis S. Prahl, Patrick F. Bangasser, Lauren E. Stopfer, Mahya Hemmat, Forest M. White, Steven S. Rosenfeld, David J. Odde

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Microtubule-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. Prahl et al. examine the mechanisms by which microtubule-targeting drugs inhibit glioma cell migration. They find that dynamic microtubules regulate actin-based protrusion dynamics that facilitate cell polarity and migration. Changes in net microtubule assembly alter cell traction forces via signaling-based regulation of a motor-clutch system.

Original languageEnglish (US)
Pages (from-to)2591-2604.e8
JournalCell reports
Volume25
Issue number9
DOIs
StatePublished - Nov 27 2018

Keywords

  • actin
  • cell migration
  • computational modeling
  • cytoskeletal crosstalk
  • mechanotransduction
  • microtubule
  • microtubule-targeting agent
  • paclitaxel
  • receptor tyrosine kinase
  • vinblastine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Prahl, L. S., Bangasser, P. F., Stopfer, L. E., Hemmat, M., White, F. M., Rosenfeld, S. S., & Odde, D. J. (2018). Microtubule-Based Control of Motor-Clutch System Mechanics in Glioma Cell Migration. Cell reports, 25(9), 2591-2604.e8. https://doi.org/10.1016/j.celrep.2018.10.101