Leading cells require LIMK for matrix degradation and invadopodia formation during collective cell migration

Ang Li

Artym

Bagheri-Yarmand

Benitah

Buccione

Cano

Coleman

Copeland

Cukierman

Daniel R. Croft

Davila

Deryugina

Diane Crighton

Ding

Doyle

Elisabeth Trivier

Erik A. Sahai

Friedl

Gaggioli

Geneste

Grant Wickman

Hall

Hanahan

Hawkins

Hennigan

Hooper

Horita

Ireen König

Itoh

John Dawson

June Munro

Kleinman

Kobayashi

Kunigal

Kurt I. Anderson

Laura Machesky

Lindenmeyer

Linder

Lizárraga

Michael F. Olson

Mishima

Nishita

Okamoto

Olson

Oser

Pierre Morin

Poincloux

Rebecca W. Scott

Riento

Ross-Macdonald

Sahai

Scher

Schoumacher

Scott

Spudich

Steven Hooper

Stylli

van Rheenen

Van Troys

Vega

Vlecken

Walker

Wang

Wolf

Wyckoff

Yamaguchi

Yoshioka

Zebda

English

PubMed

LIM kinases 1 and 2 (LIMK1/2) are centrally positioned regulators of actin cytoskeleton dynamics. Using siRNA-mediated knockdown or a novel small molecule inhibitor, we show LIMK is required for path generation by leading tumor cells and nontumor stromal cells during collective tumor cell invasion. LIMK inhibition lowers cofilin phosphorylation, F-actin levels, serum response factor transcriptional activity and collagen contraction, and reduces invasion in three-dimensional invasion assays. Although motility was unaffected, LIMK inhibition impairs matrix protein degradation and invadopodia formation associated with significantly faster recovery times in FRAP assays indicative of reduced F-actin stability. When LIMK is knocked down in MDA-MB-231 cells, they lose the ability to lead strands of collectively invading cells. Similarly, when LIMK activity is blocked in cancer-associated fibroblasts, they are unable to lead the collective invasion of squamous carcinoma cells in an organotypic skin model. These results show that LIMK is required for matrix remodeling activities for path generation by leading cells in collective invasion.</jats:p

Crossref

The Journal of Cell Biology

LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells

LIM kinases 1 and 2 (LIMK1/2) are centrally positioned regulators of actin cytoskeleton dynamics. Using siRNA-mediated knockdown or a novel small molecule inhibitor, we show LIMK is required for path generation by leading tumor cells and nontumor stromal cells during collective tumor cell invasion. LIMK inhibition lowers cofilin phosphorylation, F-actin levels, serum response factor transcriptional activity and collagen contraction, and reduces invasion in three-dimensional invasion assays. Although motility was unaffected, LIMK inhibition impairs matrix protein degradation and invadopodia formation associated with significantly faster recovery times in FRAP assays indicative of reduced F-actin stability. When LIMK is knocked down in MDA-MB-231 cells, they lose the ability to lead strands of collectively invading cells. Similarly, when LIMK activity is blocked in cancer-associated fibroblasts, they are unable to lead the collective invasion of squamous carcinoma cells in an organotypic skin model. These results show that LIMK is required for matrix remodeling activities for path generation by leading cells in collective invasion

Scott, R.W.

Hooper, S.

Crighton, D.

Li, A.

Konig, I.

Munro, J.

Trivier, E.

Wickman, G.

Morin, P.

Croft, D.R.

Dawson, J.

Machesky, L.

Anderson, K.I.

Sahai, E.A.

Olson, M.F.

Enlighten: Publications

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Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev.

Nischarin inhibits LIM kinase to regulate cofilin phosphorylation and cell invasion.

http://jcb.rupress.org/content/jcb/191/1/169.full.pdf

LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells

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