期刊
DEVELOPMENTAL CELL
卷 48, 期 3, 页码 313-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2018.12.018
关键词
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资金
- American Cancer Society [129351-PF-16-024-01-CSM]
- Leukemia and Lymphoma Society [3601-11/388-0036]
- National Cancer Institute [4R00CA154870-03]
- American Cancer Society
- National Institutes of Health [F32GM103148, NIGMS R35, MIRA GM118049, R21HD084290]
- Foundation Association pour la Recherche sur le Cancer (ARC)
- Idex [ANR-10-IDEX-0001-02 PSL]
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.
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