Universität zu Köln

Gaiko-Shcherbak, Aljona, Eschenbruch, Julian ORCID: 0000-0002-3430-3590, Kronenberg, Nils M., Teske, Michael ORCID: 0000-0002-6998-2036, Wolters, Benjamin, Springer, Ronald ORCID: 0000-0002-9655-3384, Gather, Malte C., Merkel, Rudolf ORCID: 0000-0003-3178-3282, Hoffmann, Bernd ORCID: 0000-0002-3803-8835 and Noetzel, Erik (2021). Cell Force-Driven Basement Membrane Disruption Fuels EGF- and Stiffness-Induced Invasive Cell Dissemination from Benign Breast Gland Acini. Int. J. Mol. Sci., 22 (8). BASEL: MDPI. ISSN 1422-0067

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gaiko-Shcherbak, Aljona UNSPECIFIED UNSPECIFIED UNSPECIFIED Eschenbruch, Julian UNSPECIFIED orcid.org/0000-0002-3430-3590 UNSPECIFIED Kronenberg, Nils M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Teske, Michael UNSPECIFIED orcid.org/0000-0002-6998-2036 UNSPECIFIED Wolters, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Springer, Ronald UNSPECIFIED orcid.org/0000-0002-9655-3384 UNSPECIFIED Gather, Malte C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkel, Rudolf UNSPECIFIED orcid.org/0000-0003-3178-3282 UNSPECIFIED Hoffmann, Bernd UNSPECIFIED orcid.org/0000-0002-3803-8835 UNSPECIFIED Noetzel, Erik UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-582782
DOI:	10.3390/ijms22083962
Journal or Publication Title:	Int. J. Mol. Sci.
Volume:	22
Number:	8
Date:	2021
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	1422-0067
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MATRIX STIFFNESS; TUMOR-CELLS; KEY; MORPHOGENESIS; ADHESION; PROGRESSION; MIGRATION; CUES Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58278