Journal
JOURNAL OF CELL BIOLOGY
Volume 210, Issue 6, Pages 1013-1031Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201502040
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Funding
- Wellcome Trust [090453/Z/09/Z, 090453/Z/09/A]
- Worldwide Cancer Research [14-1226]
- European Research Council [ERC-2011-StG-282059]
- Dowager Countess Eleanor Peel Trust [TH-PRCL.FID2228]
- Wellcome Trust Centre for Cell-Matrix Research [088785/Z/09/Z]
- MRC [MC_U105178788, G0400153] Funding Source: UKRI
- Wellcome Trust [090453/Z/09/A, 090453/Z/09/Z] Funding Source: Wellcome Trust
- British Heart Foundation [PG/11/123/29317] Funding Source: researchfish
- Medical Research Council [G0400153, MC_U105178788] Funding Source: researchfish
- Worldwide Cancer Research [14-1226] Funding Source: researchfish
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Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of alpha 5 beta 1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP-alpha 5 beta 1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo.
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