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Our article in the International Journal of Molecular Sciences on cell force-driven BM disruption and cell invasion:

Breast Cancer is the most diagnosed malignancy in women worldwide. The mortality rate raises significantly in patients diagnosed with invasive tumor sates. A better understanding of cell invasion mechanisms is essential for developing therapeutic approaches to block tumor progression effectively. Spatially and temporally fine-tuned extracellular cues, such as tissue stiffness and the presence of soluble growth factors, fundamentally influence the morphology and function of breast epithelial cells and are crucial for the maintenance of tissue homeostasis and organ function.

invasiver BrustzellazinusAn invasive breast cell acinus interacts with an elastomeric substrate, which is used for the measurment of cell forces (grey). A tumor-like stiffness and epidermal growth factor stimulation induced mechanical BM-weakeing. The BM scaffold (green) is locally disrupted at several spots and collective cell (cyan: cell nuclei, red: actin cytoskeleton) transmigration into the microenvironment is evident. 3D reconstruction of an immune fluorescent microscopic image stack.

These cellular cues are deregulated in tumor development and drive tumor progression. Healthy epithelial cells are surrounded by an intact basement membrane (BM). This BM consists of a dense multi-protein scaffold and separates breast epithelial cells from the surrounding extracellular matrix (ECM). The initial step of cancer invasion is marked by local BM disruption paving the way for tumor cell transmigration.

In our publication Dr. Noetzel-Reiss describes, together with his colleagues and his cooperation partners Dr. Nils Kronenberg and Prof. Malte Gather (University of Cologne), the mechanical forces that benign breast epithelial cells can activate when influenced by tumor-like ECM stiffness and growth factor stimulation. As a cell model, we analyzed breast cell acini covered with a mechanically robust BM scaffold. ECM-stiffening and growth factor stimulation induce an invasive cell behavior resulting in BM holes through which cells can transmigrate into the ECM space. We combined state-of-the-art mechanobiological techniques to show that breast acini exert high cell contractility-based force on their BM when triggered by tumor-like ECM cues. Further, breast acini form BM-penetrating protrusions to sense the ECM stiffness (mechanosensation). These protrusions generate additional mechanical BM stress in tumor-like ECM conditions, thereby contributing to the BM-weakening process. Generally, invasive tumor cells can weaken the BM structure proteolytically (enzymatically) and mechanically. An intriguing finding is that benign breast cells can initiate the invasive process solely by cell force-driven BM weakening.

Our study demonstrates that even benign, non-invasive breast epithelial cells are capable of local BM destruction and cell invasion. This early event in tumor progression could explain the clinical paradox of circulating tumor cells found in patients who suffer from pre-invasive breast lesions. Further studies should decipher the underlying mechanobiological pathways for this mechanism to identify potential molecular targets for new therapy approaches.