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Dev Cell. 2019 Feb 11;48(3):313-328.e8. doi: 10.1016/j.devcel.2018.12.018. Epub 2019 Jan 24.

Adaptive F-Actin Polymerization and Localized ATP Production Drive Basement Membrane Invasion in the Absence of MMPs.

Author information

1
Department of Biology, Regeneration Next, Duke University, Box 90338, Durham, NC 27708, USA.
2
CNRS, Laboratoire Physico Chimie Curie, Institut Curie, PSL Research Université, Paris 75005, France; Sorbonne Université, Paris 75005, France; Université Paris Descartes, Sorbonne Paris Cité, Paris 75005, France.
3
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USA.
4
CNRS, Laboratoire Physico Chimie Curie, Institut Curie, PSL Research Université, Paris 75005, France; Sorbonne Université, Paris 75005, France.
5
Department of Biology, Regeneration Next, Duke University, Box 90338, Durham, NC 27708, USA. Electronic address: david.sherwood@duke.edu.

Abstract

Matrix metalloproteinases (MMPs) are associated with decreased patient prognosis but have failed as anti-invasive drug targets despite promoting cancer cell invasion. Through time-lapse imaging, optical highlighting, and combined genetic removal of the five MMPs expressed during anchor cell (AC) invasion in C. elegans, we find that MMPs hasten invasion by degrading basement membrane (BM). Though irregular and delayed, AC invasion persists in MMP- animals via adaptive enrichment of the Arp2/3 complex at the invasive cell membrane, which drives formation of an F-actin-rich protrusion that physically breaches and displaces BM. Using a large-scale RNAi synergistic screen and a genetically encoded ATP FRET sensor, we discover that mitochondria enrich within the protrusion and provide localized ATP that fuels F-actin network growth. Thus, without MMPs, an invasive cell can alter its BM-breaching tactics, suggesting that targeting adaptive mechanisms will be necessary to mitigate BM invasion in human pathologies.

KEYWORDS:

ATP transport; actin dynamics; basement membrane; invasion; live imaging; matrix metalloproteinase; mitochondria

PMID:
30686527
PMCID:
PMC6372315
[Available on 2020-02-11]
DOI:
10.1016/j.devcel.2018.12.018
[Indexed for MEDLINE]

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