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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Kelley, LC; Chi, Q; Cáceres, R; Hastie, E; Schindler, AJ; Jiang, Y; Matus, DQ; Plastino, J; Sherwood, DR

Published Date

  • February 2019

Published In

Volume / Issue

  • 48 / 3

Start / End Page

  • 313 - 328.e8

PubMed ID

  • 30686527

Pubmed Central ID

  • 30686527

Electronic International Standard Serial Number (EISSN)

  • 1878-1551

International Standard Serial Number (ISSN)

  • 1534-5807

Digital Object Identifier (DOI)

  • 10.1016/j.devcel.2018.12.018

Language

  • eng