@phdthesis{19745,
  abstract     = {Cell migration is a crucial process in animal development and maintenance. It is incredibly
heterogeneous, with different cell types utilizing fundamentally distinct migration strategies.
The strategies also depend on the cellular microenvironment, where cells can switch between
migration modes as they encounter new environmental cues. In this thesis, we investigated
how dendritic cells adapt their migration strategy when encountering geometrically,
mechanically and chemically distinct environments.
When dendritic cells are embedded in a homogeneous fibrous network, they migrate in a fast
and directional amoeboid manner. In this migration strategy, extracellular proteolysis and
integrin-mediated adhesions are dispensable. Instead, the cells use topography of the
environment to propel their cell body forward. To migrate efficiently in the maze of different
pore sizes, they position the nucleus ahead of the microtubule organizing center (MTOC) and
use it to gauge the pores to identify the path of least resistance. Our aim was to identify
whether dendritic cells adapt their migration strategy when encountering asymmetrical
transitions into much denser environments with limited choice of large pores. In such invasive
transitions it is unclear if the cells can cross tight pores without the use of adhesions and
extracellular proteolysis and whether they maintain the nucleus in the cell front.
Using various cell migration assays such as fibrous 3D collagen gels, geometrically defined
microchannels with constrictions and simplistic under agarose migration assay, we provide
a comprehensive characterization of invasive migration of dendritic cells. We show that
during invasion the cells stall and stretch, reflecting the difficulty to translocate the bulky cell
body into the dense environment. In collagen gels, we show that dendritic cells can invade
without proteolysis and adhesions. Instead, they utilize contractility, which can lead to largescale collagen compressions. During invasion, the nucleus stalls at tight constrictions, leading
to a transient organelle reorientation. To resolve the stalling, upregulated rear contractility is
required. This contractile force is simultaneously necessary for reverting the nucleus back to
the cell front after invasion and maintaining this positioning during permissive migration.
A functional role of the reorientation was uncovered in the first collaboration project.
A prominent central actin pool was identified around the MTOC, especially pronounced in
dense and compressive environments. The actin pool was shown to generate pushing forces
to dilate the space for cell translocation. These forces are only necessary in non-permissive
environments, where the nucleus reorients to the cell rear, allowing the actin pool to
generate space. In permissive environments where space generation is dispensable, the
MTOC is located behind the nucleus and the actin cloud has reduced intensity, allowing more
actin to be incorporated into the lamellipodium, speeding up migration.
In the second collaboration project, we investigated the effects of distinct chemical
environments on dendritic cell migration. The strikingly persistent migration of these cells
was explained by their ability to modulate and even self-generate chemokine gradients. This
allows the cells to migrate faster and more persistent in uniform chemokine fields compared
to imposed chemokine gradients. The chemokine receptor CCR7 was identified as a crucial
player in this process, both sensing the signal and internalizing the chemokine to create a sink.},
  author       = {Canigova, Nikola},
  isbn         = {978-3-99078-058-9},
  issn         = {2663-337X},
  pages        = {133},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Adaptive strategies of dendritic cell migration in response to environmental cues}},
  doi          = {10.15479/AT-ISTA-19745},
  year         = {2025},
}

@article{14274,
  abstract     = {Immune responses rely on the rapid and coordinated migration of leukocytes. Whereas it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how these gradients are generated, maintained, and modulated. By combining experimental data with theory on leukocyte chemotaxis guided by the G protein–coupled receptor (GPCR) CCR7, we demonstrate that in addition to its role as the sensory receptor that steers migration, CCR7 also acts as a generator and a modulator of chemotactic gradients. Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) effectively internalize the receptor and ligand as part of the canonical GPCR desensitization response. We show that CCR7 internalization also acts as an effective sink for the chemoattractant, dynamically shaping the spatiotemporal distribution of the chemokine. This mechanism drives complex collective migration patterns, enabling DCs to create or sharpen chemotactic gradients. We further show that these self-generated gradients can sustain the long-range guidance of DCs, adapt collective migration patterns to the size and geometry of the environment, and provide a guidance cue for other comigrating cells. Such a dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization.},
  author       = {Alanko, Jonna H and Ucar, Mehmet C and Canigova, Nikola and Stopp, Julian A and Schwarz, Jan and Merrin, Jack and Hannezo, Edouard B and Sixt, Michael K},
  issn         = {2470-9468},
  journal      = {Science Immunology},
  keywords     = {General Medicine, Immunology},
  number       = {87},
  publisher    = {American Association for the Advancement of Science},
  title        = {{CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration}},
  doi          = {10.1126/sciimmunol.adc9584},
  volume       = {8},
  year         = {2023},
}

@phdthesis{6891,
  abstract     = {While cells of mesenchymal or epithelial origin perform their effector functions in a purely anchorage dependent manner, cells derived from the hematopoietic lineage are not committed to operate only within a specific niche. Instead, these cells are able to function autonomously of the molecular composition in a broad range of tissue compartments. By this means, cells of the hematopoietic lineage retain the capacity to disseminate into connective tissue and recirculate between organs, building the foundation for essential processes such as tissue regeneration or immune surveillance. 
Cells of the immune system, specifically leukocytes, are extraordinarily good at performing this task. These cells are able to flexibly shift their mode of migration between an adhesion-mediated and an adhesion-independent manner, instantaneously accommodating for any changes in molecular composition of the external scaffold. The key component driving directed leukocyte migration is the chemokine receptor 7, which guides the cell along gradients of chemokine ligand. Therefore, the physical destination of migrating leukocytes is purely deterministic, i.e. given by global directional cues such as chemokine gradients. 
Nevertheless, these cells typically reside in three-dimensional scaffolds of inhomogeneous complexity, raising the question whether cells are able to locally discriminate between multiple optional migration routes. Current literature provides evidence that leukocytes, specifically dendritic cells, do indeed probe their surrounding by virtue of multiple explorative protrusions. However, it remains enigmatic how these cells decide which one is the more favorable route to follow and what are the key players involved in performing this task. Due to the heterogeneous environment of most tissues, and the vast adaptability of migrating leukocytes, at this time it is not clear to what extent leukocytes are able to optimize their migratory strategy by adapting their level of adhesiveness. And, given the fact that leukocyte migration is characterized by branched cell shapes in combination with high migration velocities, it is reasonable to assume that these cells require fine tuned shape maintenance mechanisms that tightly coordinate protrusion and adhesion dynamics in a spatiotemporal manner. 
Therefore, this study aimed to elucidate how rapidly migrating leukocytes opt for an ideal migratory path while maintaining a continuous cell shape and balancing adhesive forces to efficiently navigate through complex microenvironments. 
The results of this study unraveled a role for the microtubule cytoskeleton in promoting the decision making process during path finding and for the first time point towards a microtubule-mediated function in cell shape maintenance of highly ramified cells such as dendritic cells. Furthermore, we found that migrating low-adhesive leukocytes are able to instantaneously adapt to increased tensile load by engaging adhesion receptors. This response was only occurring tangential to the substrate while adhesive properties in the vertical direction were not increased. As leukocytes are primed for rapid migration velocities, these results demonstrate that leukocyte integrins are able to confer a high level of traction forces parallel to the cell membrane along the direction of migration without wasting energy in gluing the cell to the substrate. 
Thus, the data in the here presented thesis provide new insights into the pivotal role of cytoskeletal dynamics and the mechanisms of force transduction during leukocyte migration. 
Thereby the here presented results help to further define fundamental principles underlying leukocyte migration and open up potential therapeutic avenues of clinical relevance.
},
  author       = {Kopf, Aglaja},
  isbn         = {978-3-99078-002-2},
  issn         = {2663-337X},
  keywords     = {cell biology, immunology, leukocyte, migration, microfluidics},
  pages        = {171},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{The implication of cytoskeletal dynamics on leukocyte migration}},
  doi          = {10.15479/AT:ISTA:6891},
  year         = {2019},
}