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Research Training Network on Integrated Component Cycling in Epithelial Cell Motility

Periodic Reporting for period 2 - InCeM (Research Training Network on Integrated Component Cycling in Epithelial Cell Motility)

Reporting period: 2017-01-01 to 2018-12-31

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 were pursued involving experimentalists competent in different techniques and theoreticians with expertise in analysing multimodal experimental datasets and integrating them into multi-scale models. InCeM achieved this by bringing together these experts and training a new generation of researchers. InCeM developed and used novel devices for multimodal and multidimensional recording techniques of subcellular processes, extracted quantitative data from these recordings and measurements, and integrated large datasets into mechanistic mathematical models. These models were validated experimentally and can be used for tuning cell migration in vitro and in vivo to benefit tumour patients and the millions of patients suffering from chronic wounds.
"The following list highlights major accomplishments of InCeM:

- 14 of the recruited ESRs already have or are in the process of submitting their PhD thesis.

- Intense supervision and mentoring
- Six subgroup meetings
- A three-week workshop at the renowned Isaac Newton Institute for Mathematical Sciences in Cambridge
- Two international symposia in Vienna and Aachen with leading experts from all over the world
- Multiple secondments for each ESR to master state-of-the-art techniques
- More than 120 training activities for complementary 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 a chemotaxis slide with a migration arena for studying chemotaxis of cells migrating in a 2D or 3D environment
- 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
- Detection of collective cell migration in wounded murine skin
- 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
- Analysis of keratin retraction upon laser ablation

Theoretical research
- 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
- 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
- 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
- Building a computational model for interaction between a polymerizing network of actin filaments and a membrane
- Single filament analysis"
InCeM's research provided novel devices and software that 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 are 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 is therefore of tremendous socio-economic relevance.
An impact was also achieved by the newly-developed cell-based assays, especially those for chemotaxis. They 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 advanced the development of new mathematics and numerical methods for 2- and 3-D cell migration through isotropic as well as non-isotropic environments. InCeM's research outcomes also benefits one of the greatest challenges faced by the scientific community at large, namely how to deal with large datasets. Especially challenging was and still remains the multimodal nature of the obtained datasets. InCeM provided research-recipes on novel methods for analyses and high performance computing using such datasets (experimentally and computationally generated). The solutions provided by InCeM yield general strategies to extract useful information for deriving models with predictive power. The insights have fundamental impact in medicine and beyond.

InCeM shaped and trained 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.
Scheme of InCeM's multidisciplinary approach to observe, analyse, model and modify cell migration.