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Mechanical control of biological function

Periodic Reporting for period 3 - MECHANO-CONTROL (Mechanical control of biological function)

Reporting period: 2019-07-01 to 2020-12-31

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.
The technology required to generate photo-sensitive adhesive ligands and hydrogels has been developed, and is now being tested in relevant 3D organoid models. Further and at the molecular scale, a highly novel role of molecular mechanics in nucleocytoplasmic transport has been unveiled. This has important implications in terms of regulation of cell function, and is currently being studied. In parallel, mechanosensing responses, and their impact in breast cancer biology, have been characterized further, from the subcellular to the organoid scale, including the interaction between cells and hydrogels coated with ligands. Cells are indeed able to interact with these environments, exhibiting diverse and sometimes counter-intuitive responses when exposed to different mechanical and adhesive cues. In this regard, promising interactions for the potential development of drugs have been identified, and computational modelling has been carried out to establish drug design. Importantly, drugs inhibiting key adhesive interactions have been developed and tested. Additionally, new tumour organoid and grafting tools have been developed. New animal models, microarray sets, 3D reconstruction tools, and inducible loss of function tools have been implemented. Further, we have studied the role of mechanically-related targets such YAP, Loxl3, Id2 and FER Kinase. Finally, we have developed computational tools to model molecular bond clusters. Further, an ambitious new theoretical model is being developed to integrate findings from the subcellular to the organoid scale, to predict tumour invasion.
The last decade has brought extensive evidence demonstrating that mechanical forces transmitted through cell-matrix and cell-cell adhesions drive fundamental processes in development, tumourigenesis, and wound healing. A major potential in oncology, regenerative medicine, and biomaterial design could thus be harnessed by the understanding and control of biological adhesion and mechanics. However, such understanding and control remain unattained as they require the generation of knowledge and technologies operating hierarchically from the scale of molecules to that of organs. This technology is currently unavailable due to the complexity, multi-scale nature, and interdisciplinarity of the phenomena involved. At the nanometre level, cells adhere to other cells and their surrounding extracellular matrix through specific molecules such as integrins or cadherins. The nano-mechanical properties under force of adhesive molecular links determine cell response and the activations of oncogenes such as YAP. At the micrometre level, the collective action of adhesive molecules enables cells not only to remain cohesive with their environment but to actively feel and respond to it, by combining both biochemical signalling and biophysical responses to mechanical forces. At the millimetre level, the again collective action and interactions among large ensembles of cells generates emerging behaviours that define tissue architecture and function. Finally, at the meter scale the adhesive interactions acting at the molecular, cellular, and tissue level integrate to enable functional organs, and functional organisms.

Our expected results are the construction of a body of knowledge and technology that encompasses biomechanics from the single molecule to whole organ scale, and the demonstration that it can be harnessed to control biological function in general, and breast cancer in particular. This will include scientific knowledge, experimental and computational technologies spanning from the molecule to the organism. Due to this hierarchical, multi-scale approach to understand and control tissue and organ behaviour, we aim to provide a rigorous, mechanistic and technologic baseline for tissue mechanics and cohesiveness with the potential to control and predict the outcome of any morphogenetic process. Specifically, we will focus on breast cancer as a proof-of-concept system.

Since mechanical forces transmitted through adhesive links are crucial in cancer, development, and wound healing, approaches based on inhibiting adhesion (for oncology applications) and on promoting it (for implants) have already been attempted. However, those approaches often fail because merely inhibiting adhesion in a tumour may promote metastasis, and because certain types of adhesion in implants may promote rejection. Because we have no mechanistic knowledge of how mechanics and adhesion drive biological response, current development is based on trial-and-error approaches, often leading resource waste and ineffective results. We propose to shift this paradigm, providing the techniques and mechanisms that will allow not merely to inhibit or promote adhesion, but to steer and tune mechanical and adhesive signals in the proper direction.

In terms of the implications of the project so far, our developed hydrogels, with the potential ability to tune adhesive and mechanical properties, have a major potential to be used in drug screening in cancer. This potential is further enhanced by all the biological characterization work being carried out by the consortium. In this regard, a patent has been filed. Additionally, we have identified a particularly promising molecular interaction involved in mechanical responses, and we are developing drugs to target it. A FET Launchpad was proposed by IBEC related to this, which was funded.
Project Summary