Two more exchanges within the Mechano·Control consortium

IBEC is hosting two members from the Mechano·Control network. On the one hand, Dimitri Kaurin, PhD student from Marino Arroyo group at Universitat Politècnica de Catalunya (UPC) that will be staying at IBEC for at least one year and on the other hand, Amy Beedle, postdoc from Sergi Garcia-Manyes at Kings College London (KCL).

Dimitri Kaurin started his stay at Pere Roca-Cusachs’ laboratory in December 2018 and it is planned to be for at least a year. One of the objectives of Dimitri’s stay is to work on a protocol to study cell-cell adhesion using a controlled system based on lipid bilayers of controlled viscosity. “Using AFM technique, we expect to access some information about cell-cell adhesion under force” says Dimitri. In the context of this research he will also visit Manuel Salmeron laboratory in Glasgow University this march to learn some techniques about functionalizing lipid bilayers with cadherins.


Dimitri Kaurin working in the laboratory at IBEC

On the other hand, Amy Beedle arrived this past January to Pere Roca-Cusachs’ laboratory. In the Garcia-Manyes lab Amy was looking at how mechanical forces can trigger conformational changes in individual proteins. Here at IBEC, she wants to incorporate the results at the single molecule level with the cellular level, to try to understand how individual bonds and proteins can contribute to cellular mechanosensing. “My aim is to expand my expertise in single molecule force spectroscopy to a larger cellular context” adds Amy.

Amy Beedle working in the laboratory at IBEC

This is the first time that both UPC and KCL teams meet with IBEC to share skills and ideas within the project’s framework.


Cadherin mechanotransduction in leader-follower cell specification during collective migration

A review article by Antoine A. Khalil and Johan de Rooij from UMC Utrecht have appeared in the Experimental Cell Research section of Elsevier

Collective invasion drives the spread of multicellular cancer groups, into the normal tissue surrounding several epithelial tumors. Collective invasion recapitulates various aspects of the multicellular organization and collective migration that take place during normal development and repair. Collective migration starts with the specification of leader cells in which a polarized, migratory phenotype is established.

Leader cells initiate and organize the migration of follower cells, to allow the group of cells to move as a cohesive and polarized unit. Leader-follower specification is essential for coordinated and directional collective movement. Forces exerted by cohesive cells represent key signals that dictate multicellular coordination and directionality. Physical forces originate from the contraction of the actomyosin cytoskeleton, which is linked between cells via cadherin-based cell-cell junctions.

The cadherin complex senses and transduces fluctuations in forces into biochemical signals that regulate processes like cell proliferation, motility and polarity. With cadherin junctions being maintained in most collective movements the cadherin complex is ideally positioned to integrate mechanical information into the organization of collective cell migration. Here we discuss the potential roles of cadherin mechanotransduction in the diverse aspects of leader versus follower cell specification during collective migration and neoplastic invasion.



Khalil, A.A., Experimental Cell Research, https://doi.org/10.1016/j.yexcr.2019.01.006

Presentation

Mechanical forces transmitted through specific molecular bonds drive biological function, and their understanding and control hold an uncharted potential in oncology, regenerative medicine and biomaterial design. However, this potential has not been realised, because it requires developing and integrating disparate technologies to measure and manipulate mechanical and adhesive properties from the nanometre to the metre scale. We propose to address this challenge by building an interdisciplinary research community with the aim of understanding and controlling cellular mechanics from the molecular to the organism scale.

At the nanometric molecular level, we will develop cellular microenvironments enabled by peptidomimetics of cell-cell and cell-matrix ligands, with defined mechanical and adhesive properties that we will dynamically control in time and space trough photo-activation. The properties under force of the molecular bonds involved will be characterized using single-molecule atomic force microscopy and magnetic tweezers.

At the cell-to-organ scale, we will combine controlled microenvironments and interfering strategies with the development of techniques to measure and control mechanical forces and adhesion in cells and tissues, and to evaluate their biological response.

At the organism scale, we will establish how cellular mechanics can be controlled, by targeting specific adhesive interactions, to impair or abrogate breast tumour progression in a mouse model.

At all stages and scales of the project, we will integrate experimental data with multiscale computational modelling to establish the rules driving biological response to mechanics and adhesion. With this approach, we aim to develop specific therapeutic approaches beyond the current paradigm in breast cancer treatment. Beyond breast cancer, the general principles targeted by our technology will have high applicability in oncology, regenerative medicine and biomaterials.