Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion

K Wolf, YI Wu, Y Liu, J Geiger, E Tam, C Overall… - Nature cell …, 2007 - nature.com
K Wolf, YI Wu, Y Liu, J Geiger, E Tam, C Overall, MS Stack, P Friedl
Nature cell biology, 2007nature.com
Invasive cell migration through tissue barriers requires pericellular remodelling of
extracellular matrix (ECM) executed by cell-surface proteases, particularly membrane-type-1
matrix metalloproteinase (MT1-MMP/MMP-14). Using time-resolved multimodal microscopy,
we show how invasive HT-1080 fibrosarcoma and MDA-MB-231 breast cancer cells
coordinate mechanotransduction and fibrillar collagen remodelling by segregating the
anterior force-generating leading edge containing β1 integrin, MT1-MMP and F-actin from a …
Abstract
Invasive cell migration through tissue barriers requires pericellular remodelling of extracellular matrix (ECM) executed by cell-surface proteases, particularly membrane-type-1 matrix metalloproteinase (MT1-MMP/MMP-14). Using time-resolved multimodal microscopy, we show how invasive HT-1080 fibrosarcoma and MDA-MB-231 breast cancer cells coordinate mechanotransduction and fibrillar collagen remodelling by segregating the anterior force-generating leading edge containing β1 integrin, MT1-MMP and F-actin from a posterior proteolytic zone executing fibre breakdown. During forward movement, sterically impeding fibres are selectively realigned into microtracks of single-cell calibre. Microtracks become expanded by multiple following cells by means of the large-scale degradation of lateral ECM interfaces, ultimately prompting transition towards collective invasion similar to that in vivo. Both ECM track widening and transition to multicellular invasion are dependent on MT1-MMP-mediated collagenolysis, shown by broad-spectrum protease inhibition and RNA interference. Thus, invasive migration and proteolytic ECM remodelling are interdependent processes that control tissue micropatterning and macropatterning and, consequently, individual and collective cell migration.
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