Schmidt Lab

“Hexanematic crossover in epithelial monolayers depends on cell adhesion and cell density”

Julia Eckert, Benoît Ladoux, René-Marc Mège, Luca Giomi & Thomas Schmidt

Changes in tissue geometry during developmental processes are associated with collective migration of cells. Recent experimental and numerical results suggest that these changes could leverage on the coexistence of nematic and hexatic orientational order at different length scales. How this multiscale organization is affected by the material properties of the cells and their sub- strate is presently unknown. In this study, we address these questions in monolayers of Madin-Darby canine kidney cells having various cell densities and molecular repertoires. At small length scales, confluent monolayers are characterized by a prominent hexatic order, independent of the presence of E- cadherin, monolayer density, and underlying substrate stiffness. However, all three properties affect the meso-scale tissue organization. The length scale at which hexatic order transits to nematic order, the “hexanematic” crossover scale, strongly depends on cell-cell adhesions and correlates with monolayer density. Our study demonstrates how epithelial organization is affected by mechanical properties, and provides a robust description of tissue organiza- tion during developmental processes.

To be read in: Nat Comm 14, 5762

Congrats to Julia!

Integrin alpha-2 popped up in a screen of aggressive and chemoresistant PDAC cancers. In this study of Alessandro and Cecilia we validated the results we obtained in the RNA screen with various methods. Again we find a correlation between cell mechanics, aggressiveness, and chemoresistance. More to come …

Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC).

Gregori, A.; Bergonzini, C.; Capula, M.; Mantini, G.; Khojasteh-Leylakoohi, F.; Comandatore, A.; Khalili-Tanha, G.; Khooei, A.; Morelli, L.; Avan, A.; Danen, E.H.; Schmidt, T.; Giovannetti, E.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and chemoresistant cancer, with a poor overall survival. The stiff stroma surrounding PDAC is known to be involved in chemoresistance via mechanical cues, although the mechanisms behind it are poorly understood. Here, we investigated whether integrin alpha 2 (ITGA2), a mechanical sensor of stiffness, correlated with poor prognosis and whether matrix stiffness could trigger chemoresistance to gemcitabine. By assessing two cohorts of patients, we observed a poorer prognosis for the high ITGA2 expression group. An increase in matrix stiffness prompted cancer cells to express more ITGA2 and become chemoresistant. ITGA2 might therefore be an interesting therapeutic target to overcome resistance to gemcitabine.

Cancers (2023) 15:628 (doi:10.3390/cancers15030628)

We developed a novel methodology to count the number of molecules in a STORM image. That allowed us to address the stoichiometry of adhesion proteins in focal adhesions. It appeared that the stoichiometry in FAK is independent on the force exerted by the cell.

Substrate rigidity modulates traction forces and stoichiometry of cell–matrix adhesions.

Hayri E. Balcioglu, Rolf Harkes, Erik H. J. Danen, and Thomas Schmidt.

In cell–matrix adhesions, integrin receptors and associated proteins provide a dynamic coupling of the extracellular matrix (ECM) to the cytoskeleton. This allows bidirectional transmission of forces between the ECM and the cytoskeleton, which tunes intracellular signaling cascades that control survival, proliferation, differentiation, and motility. The quantitative relationships between recruitment of distinct cell–matrix adhesion proteins and local cellular traction forces are not known. Here, we applied quantitative super-resolution microscopy to cell–matrix adhesions formed on fibronectin-stamped elastomeric pillars and developed an approach to relate the number of talin, vinculin, paxillin, and focal adhesion kinase (FAK) molecules to the local cellular traction force. We find that FAK recruitment does not show an association with traction-force application, whereas a ∼60 pN force increase is associated with the recruitment of one talin, two vinculin, and two paxillin molecules on a substrate with an effective stiffness of 47 kPa. On a substrate with a fourfold lower effective stiffness, the stoichiometry of talin:vinculin:paxillin changes to 2:12:6 for the same ∼60 pN traction force. The relative change in force-related vinculin recruitment indicates a stiffness-dependent switch in vinculin function in cell–matrix adhesions. Our results reveal a substrate-stiffness-dependent modulation of the relationship between cellular traction-force and the molecular stoichiometry of cell–matrix adhesions.

doi: 10.1063/5.0077004

Cell-cell and cell-matrix interactions are governed by interactions between individual molecules. But how does a tissue emerge from those localized and individual events? In this review we summarize our current understanding.

Holding it together: when cadherin meets cadherin

Arslan, F. N., J. Eckert, T. Schmidt, and C. P. Heisenberg

Intercellular adhesion is the key to multicellularity, and its malfunction plays an important role in various developmental and disease-related processes. Although it has been intensively studied by both biologists and physicists, a commonly accepted definition of cell-cell adhesion is still being debated. Cell-cell adhesion has been described at the molecular scale as a function of adhesion receptors controlling binding affinity, at the cellular scale as resistance to detachment forces or modulation of surface tension, and at the tissue scale as a regulator of cellular rearrangements and morphogenesis. In this review, we aim to summarize and discuss recent advances in the molecular, cellular, and theoretical description of cell-cell adhesion, ranging from biomimetic models to the complexity of cells and tissues in an organismal context. In particular, we will focus on cadherin-mediated cell-cell adhesion and the role of adhesion signaling and mechanosensation therein, two processes central for understanding the biological and physical basis of cell-cell adhesion.

doi: 10.1016/j.bpj.2021.03.025