@article{21384, abstract = {Cell migration in vivo is often guided by chemical signaling, i.e., chemotaxis. For immune cells performing chemotaxis in the organism, this process is influenced by the complex geometry of the tissue environment. In this study, we use a theoretical model of branched cell migration on a network to explore the cellular response to chemical gradients. The model predicts the response of a branched cell to a chemical gradient: how the cell reorients its internal polarity and how it navigates through a complex environment up a chemical gradient. We then compare the model’s predictions with experimental observations of neutrophils migrating to the site of a laser-inflicted wound in a zebrafish larva fin, and neutrophils migrating in vitro inside a regular lattice of pillars. We find that the model captures the details of the subcellular response to the chemokine gradient, as well as qualitative characteristics of the large-scale migration, suggesting that the neutrophils behave as fast cells, which explains the functionality of these immune cells.}, author = {Liu, Jiayi and Ron, Jonathan E. and Rinaldi, Giulia and Williantarra, Ivanna and Georgantzoglou, Antonios and de Vries, Ingrid and Sixt, Michael K and Sarris, Milka and Gov, Nir S.}, issn = {1553-7358}, journal = {PLOS Computational Biology}, number = {2}, publisher = {Public Library of Science}, title = {{Modelling chemotaxis of branched cells in complex environments provides insights into immune cell navigation}}, doi = {10.1371/journal.pcbi.1013934}, volume = {22}, year = {2026}, } @phdthesis{22744, author = {Javoor, Manjunath}, isbn = {978-3-99078-090-9 }, issn = {2663-337X}, keywords = {Actin cytoskeleton, Cell migration, cryo-electron tomography}, pages = {121}, publisher = {Institute of Science and Technology Austria }, title = {{Large-scale imaging of cellular actin networks at single filament resolution using montage cryo-electron tomography}}, doi = {10.15479/AT-ISTA-22744}, year = {2026}, } @article{22963, abstract = {Although studies of tumor invasion have mainly emphasized the evolution of genetic and epigenetic heterogeneity, cellular behaviors also depend on the physical microenvironment. Yet, the tumor microenvironment is both complex and continuously remodeled, making it hard to rigorously test its causal influence on tumor dissemination. Here, we adopted a reductionist approach to studying tumor cell invasion in microengineered environments of tunable patterned geometries. We find that not only the presence of obstacles but more unexpectedly their spatial disorder causes a drastic shift from a collective to a single-cell mode of invasion—comparable in strength to loss of cell-cell adhesion. Combining live-imaging and perturbation experiments with minimal biophysical modeling, we demonstrate that cell dissemination results both from local geometrical constraints and a global integration of spatial disorder over time. We identify generic universality classes of invasion dynamics dependent on environmental geometry, enabling us to identify quantitative physical principles for tumor dissemination.}, author = {Dunajova, Zuzana and Tasciyan, Saren and Majek, Juraj and Merrin, Jack and Jenkins, Robert P. and Sahai, Erik and Sixt, Michael K and Hannezo, Edouard B}, issn = {2375-2548}, journal = {Science Advances}, number = {37}, publisher = {AAAS}, title = {{Substrate heterogeneity promotes cancer cell dissemination through interface roughening}}, doi = {10.1126/sciadv.aed0587}, volume = {12}, year = {2026}, } @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{20149, abstract = {Immune responses depend on the coordinated and efficient migration of leukocytes. These cells, which are embedded and tightly confined within tissues, must navigate and traverse diverse and complex three-dimensional environments. Leukocytes adapt their locomotory behavior to the mechanical, geometrical, and biochemical characteristics of their surroundings. In low-density environments, where the pore size of the interstitial matrix allows free passage, these cells position the nucleus directly behind the lamellipodium, the protrusive actin structure that forms the leading front of the cell. In this configuration, they use the nucleus as a gauge to identify the path of least resistance. Here, we show that in high-density environments, where the pore size precludes free passage of the cell body, leukocytes reposition the microtubule-organizing center (MTOC) and associated organelles in front of the nucleus. In this configuration, they use actin structures protruding orthogonally to the direction of migration in order to open a path for the cell body. We identify two distinct actin populations that serve this purpose at different subcellular localizations. At the leading edge, local indentation of the plasma membrane leads to recruitment of the Wiskott-Aldrich syndrome protein (WASp), which, via Arp2/3, results in the formation of individual actin foci. At the cell body, actin polymerization is triggered by DOCK8, a Cdc42 exchange factor, resulting in the formation of a central actin pool. We demonstrate that the central and peripheral actin pools are functionally communicating and that depletion of the central actin pool leads to increased actin accumulation at the cell front, resulting in excessive extension of the leading edge.}, author = {Dos Reis Rodrigues, Patricia}, issn = {2663-337X}, pages = {114}, publisher = {Institute of Science and Technology Austria}, title = {{Coordination of protrusive forces in immune cell migration }}, doi = {10.15479/AT-ISTA-20149}, year = {2025}, } @unpublished{21427, abstract = {While tumor malignancy has been extensively studied under the prism of genetic and epigenetic heterogeneity, tumor cell states also critically depend on reciprocal interactions with the microenvironment. This raises the hitherto untested possibility that heterogeneity of the untransformed tumor stroma can actively fuel malignant progression. As biological heterogeneity is inherently difficult to control, we adopted a reductionist approach and let tumor cells invade micro-engineered environments harboring obstacles with precision-controlled geometry. We find that not only the presence of obstacles, but more surprisingly their spatial disorder, causes a drastic shift from a collective to a single-cell mode of invasion – comparable in strength to cadherin loss. Combining live-imaging and perturbation experiments with minimal biophysical modeling, we demonstrate that cell detachments result both from local geometrical constraints and a global integration of spatial disorder over time. We show that different types of microenvironments map onto different universality classes of invasion dynamics - homogeneous substrates follow Kardar–Parisi–Zhang (KPZ) scaling, while disordered ones exhibit exponents consistent with KPZ with quenched disorder (KPZq). Our findings highlight generic physical principles for how the mode of cancer cell invasion depends on environmental heterogeneity, with potential implications to understand tumor evolution in vivo.}, author = {Dunajova, Zuzana and Tasciyan, Saren and Majek, Juraj and Merrin, Jack and Sahai, Erik and Sixt, Michael K and Hannezo, Edouard B}, booktitle = {bioRxiv}, title = {{Substrate heterogeneity promotes cancer cell dissemination through interface roughening}}, doi = {10.1101/2025.05.20.655037}, year = {2025}, }