Collective epithelial cell invasion overcomes mechanical barriers of collagenous extracellular matrix by a narrow tube-like geometry and MMP14-dependent local softening

Jordi Alcaraz, Hidetoshi Mori, Cyrus M. Ghajar, Doug Brownfield, Roland Galgoczy, Mina J. Bissell

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Collective cell invasion (CCI) through interstitial collagenous extracellular matrix (ECM) is crucial to the initial stages of branching morphogenesis, and a hallmark of tissue repair and dissemination of certain tumors. The collagenous ECM acts as a mechanical barrier against CCI. However, the physical nature of this barrier and how it is overcome by cells remains incompletely understood. To address these questions, we performed theoretical and experimental analysis of mammary epithelial branching morphogenesis in 3D type I collagen (collagen-I) gels. We found that the mechanical resistance of collagen-I is largely due to its elastic rather than its viscous properties. We also identified two strategies utilized by mammary epithelial cells that can independently minimize ECM mechanical resistance during CCI. First, cells adopt a narrow tube-like geometry during invasion, which minimizes the elastic opposition from the ECM as revealed by theoretical modeling of the most frequent invasive shapes and sizes. Second, the stiffness of the collagenous ECM is reduced at invasive fronts due to its degradation by matrix metalloproteinases (MMPs), as indicated by direct measurements of collagen-I microelasticity by atomic force microscopy. Molecular techniques further specified that the membrane-bound MMP14 mediates degradation of collagen-I at invasive fronts. Thus, our findings reveal that MMP14 is necessary to efficiently reduce the physical restraints imposed by collagen-I during branching morphogenesis, and help our overall understanding of how forces are balanced between cells and their surrounding ECM to maintain collective geometry and mechanical stability during CCI.

Original languageEnglish (US)
Pages (from-to)1153-1166
Number of pages14
JournalIntegrative Biology
Volume3
Issue number12
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

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Extracellular Matrix
Epithelial Cells
Collagen
Geometry
Morphogenesis
Breast
Degradation
Physical Restraint
Mechanical stability
Architectural Accessibility
Collagen Type I
Matrix Metalloproteinases
Atomic Force Microscopy
Tumors
Atomic force microscopy
Repair
Gels
Stiffness
Tissue
Membranes

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

Cite this

Collective epithelial cell invasion overcomes mechanical barriers of collagenous extracellular matrix by a narrow tube-like geometry and MMP14-dependent local softening. / Alcaraz, Jordi; Mori, Hidetoshi; Ghajar, Cyrus M.; Brownfield, Doug; Galgoczy, Roland; Bissell, Mina J.

In: Integrative Biology, Vol. 3, No. 12, 01.12.2011, p. 1153-1166.

Research output: Contribution to journalArticle

Alcaraz, Jordi ; Mori, Hidetoshi ; Ghajar, Cyrus M. ; Brownfield, Doug ; Galgoczy, Roland ; Bissell, Mina J. / Collective epithelial cell invasion overcomes mechanical barriers of collagenous extracellular matrix by a narrow tube-like geometry and MMP14-dependent local softening. In: Integrative Biology. 2011 ; Vol. 3, No. 12. pp. 1153-1166.
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