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 language | English (US) |
|---|---|
| Pages (from-to) | 2591-2604.e8 |
| Journal | Cell reports |
| Volume | 25 |
| Issue number | 9 |
| DOIs | |
| State | Published - Nov 27 2018 |
Bibliographical note
Funding Information:We thank the Odde laboratory, especially Dr. Brian Castle and Ghaidan Shamsan for technical assistance and helpful discussions, and Dr. Jay Hou for assistance with simulations. We thank Professor Margaret Titus for critically reviewing manuscript drafts. High-performance computing (HPC) resources used in this study included the Minnesota Supercomputing Institute and the Extreme Science and Engineering Discovery Environment (XSEDE) Comet HPC at the San Diego Supercomputing Center (Towns et al., 2014) through allocation MCB160194. XSEDE is supported by NSF grant (ACI-1053575). This work was supported by a 3M Science & Technology Doctoral Fellowship (to L.S.P.), NSF Graduate Research Fellowship 00039202 (to L.S.P.), a University of Minnesota UROP award (to P.F.B.), an NIH training grant (T32 ES007020) (to L.E.S.), and NIH grants (U54 CA210180 to F.M.W.; R01 NS073610 to S.S.R.; R01 CA172986 and U54 CA 210190 to D.J.O. and S.S.R.; and R01 GM076177 to D.J.O.).
Funding Information:
We thank the Odde laboratory, especially Dr. Brian Castle and Ghaidan Shamsan for technical assistance and helpful discussions, and Dr. Jay Hou for assistance with simulations. We thank Professor Margaret Titus for critically reviewing manuscript drafts. High-performance computing (HPC) resources used in this study included the Minnesota Supercomputing Institute and the Extreme Science and Engineering Discovery Environment (XSEDE) Comet HPC at the San Diego Supercomputing Center ( Towns et al., 2014 ) through allocation MCB160194. XSEDE is supported by NSF grant ( ACI-1053575 ). This work was supported by a 3M Science & Technology Doctoral Fellowship (to L.S.P.), NSF Graduate Research Fellowship 00039202 (to L.S.P.), a University of Minnesota UROP award (to P.F.B.), an NIH training grant ( T32 ES007020 ) (to L.E.S.), and NIH grants ( U54 CA210180 to F.M.W.; R01 NS073610 to S.S.R.; R01 CA172986 and U54 CA 210190 to D.J.O. and S.S.R.; and R01 GM076177 to D.J.O.).
Publisher Copyright:
© 2018 The Authors
Keywords
- actin
- cell migration
- computational modeling
- cytoskeletal crosstalk
- mechanotransduction
- microtubule
- microtubule-targeting agent
- paclitaxel
- receptor tyrosine kinase
- vinblastine