EB1 and cytoplasmic dynein mediate protrusion dynamics for efficient 3‐dimensional cell migration

Microtubules have long been implicated to play an integral role in metastatic disease, for which a critical step is the local invasion of tumor cells into the 3‐dimensional (3D) collagen‐rich stromal matrix. Here we show that cell migration of human cancer cells uses the dynamic formation of highly...

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Bibliographic Details
Published in:The FASEB journal 2018-03, Vol.32 (3), p.1207-1221
Main Authors: Jayatilaka, Hasini, Giri, Anjil, Karl, Michelle, Aifuwa, Ivie, Trenton, Nicholaus J., Phillip, Jude M., Khatau, Shyam, Wirtz, Denis
Format: Article
Language:English
Subjects:
Cell Culture Techniques - methods
Cell Movement
Cell Surface Extensions - physiology
Cytoplasmic Dyneins - metabolism
Fibrosarcoma - metabolism
Fibrosarcoma - pathology
Humans
microtubule
Microtubule-Associated Proteins - metabolism
Microtubules - metabolism
Microtubules - pathology
paclitaxel
RhoA
Tumor Cells, Cultured
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Summary:Microtubules have long been implicated to play an integral role in metastatic disease, for which a critical step is the local invasion of tumor cells into the 3‐dimensional (3D) collagen‐rich stromal matrix. Here we show that cell migration of human cancer cells uses the dynamic formation of highly branched protrusions that are composed of a microtubule core surroundedby cortical actin, a cytoskeletal organization thatis absent in cells on 2‐dimensional (2D) substrates. Microtubule plus‐end tracking protein End‐binding 1 and motor protein dynein subunits light intermediate chain 2 and heavy chain 1, which do not regulate 2D migration, critically modulate 3D migration by affecting RhoA and thus regulate protrusion branching through differential assembly dynamics of microtubules. An important consequence of this observation is that the commonly used cancer drug paclitaxel is 100‐fold more effective at blocking migration in a 3D matrix than on a 2D matrix. This work reveals the central role that microtubule dynamics plays in powering cell migration in a more pathologically relevant setting and suggests further testing of therapeutics targeting microtubules to mitigate migration.—Jayatilaka, H., Giri, A., Karl, M., Aifuwa, I., Trenton, N. J., Phillip, J. M., Khatau, S., Wirtz, D. EB1 and cytoplasmic dynein mediate protrusion dynamics for efficient 3‐dimensional cell migration. FASEB J. 32, 1207–1221 (2018). www.fasebj.org
ISSN:0892-6638
1530-6860
1530-6860
DOI:10.1096/fj.201700444RR