Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/ijms22083962
Keywords
basement membrane; mechanobiology; mechanically driven cancer progression; mechanosensing; neoplasm invasion; breast cancer invasion; cell force; mechanosensory transduction; filopodia
Funding
- Deutsche Forschungsgesellschaft (DFG, German Research Foundation) [363055819/GRK2415, SPP1782, H02384/2, ME1458/8]
- Alexander von Humboldt Stiftung (Humboldt-Professorship)
- Engineering and Physical Sciences Research Council [EP/P030017/1]
- EPSRC [EP/P030017/1] Funding Source: UKRI
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The study found that disruption of the basement membrane can lead to the transition of benign acini to invasive, while EGFR activation further compromises the barrier function of the basement membrane, promoting cancer cell invasion. Breast acini continuously sense the mechanical properties of the extracellular matrix by forming new cellular protrusions, pushing and pulling on the basement membrane and extracellular matrix.
Local basement membrane (BM) disruption marks the initial step of breast cancer invasion. The activation mechanisms of force-driven BM-weakening remain elusive. We studied the mechanical response of MCF10A-derived human breast cell acini with BMs of tuneable maturation to physical and soluble tumour-like extracellular matrix (ECM) cues. Traction force microscopy (TFM) and elastic resonator interference stress microscopy (ERISM) were used to quantify pro-invasive BM stress and protrusive forces. Substrate stiffening and mechanically impaired BM scaffolds induced the invasive transition of benign acini synergistically. Robust BM scaffolds attenuated this invasive response. Additional oncogenic EGFR activation compromised the BMs' barrier function, fuelling invasion speed and incidence. Mechanistically, EGFR-PI3-Kinase downstream signalling modulated both MMP- and force-driven BM-weakening processes. We show that breast acini form non-proteolytic and BM-piercing filopodia for continuous matrix mechanosensation, which significantly push and pull on the BM and ECM under pro-invasive conditions. Invasion-triggered acini further shear and compress their BM by contractility-based stresses that were significantly increased (3.7-fold) compared to non-invasive conditions. Overall, the highest amplitudes of protrusive and contractile forces accompanied the highest invasiveness. This work provides a mechanistic concept for tumour ECM-induced mechanically misbalanced breast glands fuelling force-driven BM disruption. Finally, this could facilitate early cell dissemination from pre-invasive lesions to metastasize eventually.
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