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InCeM Report Summary

Project ID: 642866
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - InCeM (Research Training Network on Integrated Component Cycling in Epithelial Cell Motility)

Reporting period: 2015-01-01 to 2016-12-31

Summary of the context and overall objectives of the project

Cell migration (cell motility) is fundamental for the functioning of the human body. It is crucial for tissue formation and maintenance and is needed for wound healing. Cell migration is also essential for tumour invasion and metastasis during carcinogenesis. The underlying processes for cell migration are poorly understood at the mechanistic and regulatory level because of its complexity involving multiple cellular systems that are regulated through genetic, physical and biochemical signals. Yet, an integrated view is urgently needed for predicting and manipulating cell migration as a pivotal process in both health and disease. This knowledge is expected to open new avenues for the diagnosis of human diseases, their treatment and in regenerative medicine.
To reach this goal, concerted interdisciplinary approaches are needed involving experimentalists competent in different techniques and theoreticians with expertise in analysing the multimodal experimental datasets and integrating them into multi-scale models. InCeM is dedicated to achieve this by bringing together these experts and training a new generation of researchers. Our immediate objective is to develop and use novel devices for multimodal and multidimensional recording techniques of subcellular processes, to extract quantitative data from such recordings and measurements, and to integrate the large datasets into mechanistic mathematical models. These models will be validated experimentally and used to tune cell migration in vitro and in vivo.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The following list highlights major accomplishments of InCeM during its first two years of existence.

- Selection of 30 highly-qualified ESRs from 339 qualified applications and successful employment of 15 ESRs

- Three subgroup meetings and three workshops including an international three-week workshop at the renowned Isaac Newton Institute for Mathematical Sciences in Cambridge with InCeM's ESRs, PIs and partners
- Mastering techniques at home laboratory/department and training in additional skills through secondments
- Individualised programs for skill acquisition in multiple formats

- Award to Victor Juma (ESR12) for being the best graduating student from Nairobi (05/2016)
- Award to Nadieh Kuijpers (ESR3) for her poster at the Heraeus-Seminar "Cellular Dynamics" (09/2016)

Experimental research
- Development of novel microchannels and stretching devices to study the effects of confinement and shear stress on cell motility
- Development of microfluidic systems to create defined cell clusters for investigating the effects of guidance cues on collective cell migration
- Development of an experimental model for studying filopodia structure and dynamics
- Generation of genetically identical organoids from genetic mouse models to examine the importance of actin remodelling during migration in vitro and in vivo
- Establishment of intravital microscopy to image migrating keratinocytes in the skin of living mice after wounding
- Monitoring of spatial and temporal Rho GTPase activity patterns in living keratinocytes
- Establishment of new methods to study diffusion and transport of cytoskeletal and adhesion proteins during keratinocyte migration
- First ever simultaneous monitoring of the actin and keratin cytoskeleton in migrating keratinocytes revealing divergent distribution and dynamics
- Detection of hitherto unknown chevron-like structures containing hemidesmosomal cell-extracellular matrix adhesion proteins that are transiently-formed in migrating keratinocytes
- Discovery of unexpected motility responses to laser-assisted ablation of actin stress fibres

Theoretical research
- First temporal model describing Rho activity dynamics
- Development of new image analysis tools for tracking of migrating cells and subcellular dynamics
- Development of viscoelastic-reaction-diffusion model for 3D cell migration
- Development of coupled bulk-surface partial differential equations and their numerical solutions using coupled bulk-surface finite element methods
- Development of inverse model for the recovery of traction forces during cell migration
- Development of Bayesian approach for parameter identification and model selection
- First multiparameter models for cell polarization and cell migration
- Development of user-friendly software packages for analysis of cytoskeletal network dynamics and organisation
- Formulation and application of a spring mass model for mechanical modelling of cytoskeletal filament systems
- First scripts to look at the impact of cell neighbours on cell migration in clonally diverse fields of cells
- Initiation of a model for filopodia adhesion and extension
- First steps in modelling mutual attachment of two keratin bundles with different thickness
- Building a computational model for interaction between a polymerizing network of actin filaments and a membrane.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

InCeM's research has already provided novel devices and software that will help to improve and standardize analysis of motile cell behaviour and the dynamic properties of subcellular elements in quantitative terms. It thereby opened inroads into the quantitative assessment of cellular properties that were so far out of reach for routine analyses. These approaches will become important for the characterization of tumour cells on a patient-by-patient basis with direct consequences for treatment protocols. In light of the continued increase in malignancies it will therefore be of tremendous socio-economic relevance.
An impact is also expected by the newly-developed cell-based assays, especially those for chemotaxis. They will increase the throughput and accuracy of compound screening in the pharmaceutical industry leading to reduced costs for research and development of new drugs interfering with chemotactic migration of tumour cells.
The theoretical research outcomes of InCeM will advance the development of new mathematics and numerical methods for 2- and 3-D cell migration through isotropic as well as non-isotropic environments in the short term. In the long term, InCeM's research outcomes will benefit one of the greatest challenges faced by the scientific community at large, namely how to deal with large datasets. Especially challenging is the multimodal nature of such datasets. This challenge is directly addressed in the research topic of InCeM, which is expected to provide research-recipes on novel methods for analyses and high performance computing using such datasets (experimentally and computationally generated). The solutions provided by InCeM will yield general strategies to extract useful information for deriving models with predictive power. These insights will have fundamental impact in medicine and beyond.
InCeM will shape and train a new generation of young scientists with sought-after interdisciplinary skills that span experiments, modelling, numerical methods to applications and model validation and back to refinement of experiments and modelling.

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