@article{20082,
  abstract     = {Efficient immune responses rely on the capacity of leukocytes to traverse diverse and complex tissues. To meet such changing environmental conditions, leukocytes usually adopt an ameboid configuration, using their forward-positioned nucleus as a probe to identify and follow the path of least resistance among pre-existing pores. We show that, in dense environments where even the largest pores preclude free passage, leukocytes position their nucleus behind the centrosome and organelles. The local compression imposed on the cell body by its surroundings triggers assembly of a central F-actin pool, located between cell front and nucleus. Central actin pushes outward to transiently dilate a path for organelles and nucleus. Pools of central and front actin are tightly coupled and experimental depletion of the central pool enhances actin accumulation and protrusion formation at the cell front. Although this shifted balance speeds up cells in permissive environments, migration in restrictive environments is impaired, as the unleashed leading edge dissociates from the trapped cell body. Our findings establish an actin regulatory loop that balances path dilation with advancement of the leading edge to maintain cellular coherence.},
  author       = {Dos Reis Rodrigues, Patricia and Avellaneda Sarrió, Mario and Canigova, Nikola and Gärtner, Florian R and Vaahtomeri, Kari and Riedl, Michael and De Vries, Ingrid and Merrin, Jack and Hauschild, Robert and Fukui, Yoshinori and Juanes Garcia, Alba and Sixt, Michael K},
  issn         = {1529-2916},
  journal      = {Nature Immunology},
  pages        = {1258–1266},
  publisher    = {Springer Nature},
  title        = {{Migrating immune cells globally coordinate protrusive forces}},
  doi          = {10.1038/s41590-025-02211-w},
  volume       = {26},
  year         = {2025},
}

@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},
}

@article{8988,
  abstract     = {The differentiation of cells depends on a precise control of their internal organization, which is the result of a complex dynamic interplay between the cytoskeleton, molecular motors, signaling molecules, and membranes. For example, in the developing neuron, the protein ADAP1 (ADP-ribosylation factor GTPase-activating protein [ArfGAP] with dual pleckstrin homology [PH] domains 1) has been suggested to control dendrite branching by regulating the small GTPase ARF6. Together with the motor protein KIF13B, ADAP1 is also thought to mediate delivery of the second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to the axon tip, thus contributing to PIP3 polarity. However, what defines the function of ADAP1 and how its different roles are coordinated are still not clear. Here, we studied ADAP1’s functions using in vitro reconstitutions. We found that KIF13B transports ADAP1 along microtubules, but that PIP3 as well as PI(3,4)P2 act as stop signals for this transport instead of being transported. We also demonstrate that these phosphoinositides activate ADAP1’s enzymatic activity to catalyze GTP hydrolysis by ARF6. Together, our results support a model for the cellular function of ADAP1, where KIF13B transports ADAP1 until it encounters high PIP3/PI(3,4)P2 concentrations in the plasma membrane. Here, ADAP1 disassociates from the motor to inactivate ARF6, promoting dendrite branching.},
  author       = {Düllberg, Christian F and Auer, Albert and Canigova, Nikola and Loibl, Katrin and Loose, Martin},
  issn         = {1091-6490},
  journal      = {Proceedings of the National Academy of Sciences of the United States of America},
  number       = {1},
  publisher    = {National Academy of Sciences},
  title        = {{In vitro reconstitution reveals phosphoinositides as cargo-release factors and activators of the ARF6 GAP ADAP1}},
  doi          = {10.1073/pnas.2010054118},
  volume       = {118},
  year         = {2021},
}