DCs are immune cells found in a variety of peripheral tissues, where they sample the environment in the lookout for threats such as microbial infections. When they find such threats, they subsequently migrate from the peripheral tissues to the lymph nodes where they transmit this information to T cells. These migration steps are accompanied by changes in DC shape and we set out to quantify such changes, their molecular mechanisms and long-term phenotypic and functional consequences. DC migration from the peripheral tissues to the lymph nodes requires the expression of specific chemokine receptors (CCR7) that recognize chemokine gradients guiding them to the lymphatic vessels. To understand the effects of environmentally-induced shape changes on DCs, we subjected skin DCs to various levels of physical confinement they can find in tissues and we unexpectedly uncovered a precise deformation amplitude at which DCs activate a shape-sensing mechanism that leads to an increased expression of the CCR7 chemokine receptor. This subsequently leads to the steady state migration of DCs from peripheral tissues to the lymph nodes and a global transcriptional reprogramming that is different from the one triggered upon microbial sensing. These results show that DCs have a shape-sensing mechanism that defines their migratory behaviour and immune phenotype in steady state conditions. Rather than sensing molecular biochemical signals, these cells might sense the physical constraints they encounter while patrolling their environment. These unexpected results highlight the importance of physical properties and their subsequent cues to tissue organization and function, and how these can shape immunity (published in 2024 DOI 10.1038/s41590-024-01856-3).
We also uncovered the molecular drivers of migration of cells that do not attach to surfaces, such as the two cell types we focus on in this project. These cells move through the creation of intracellular actomyosin zones of distinct rigidity: a soft front that deforms to squeeze through spaces, a rigid middle to hold its shape, and a rear that acts as the cell’s ‘muscle’ to push forward. This organization allows cells to generate force and move effectively. When physically confined, these cells can also create protrusions that eventually detach as motile cell fragments with capacity to migrate. This finding mirrors recent intravital microscopy studies in live tumors, where scientists observed cancer cells fragmenting in real time, with pieces breaking off and moving independently through tissues (published in 2024 DOI 10.1016/j.devcel.2024.06.023 ).
As stated above, we also set out to analyze the influence of physical constraints in breast cancer cells (BCCs). It has been observed that rounder BCCs are correlated with solid-like and tumor suppressive states. The transition to a malignant state is often accompanied by the acquisition of more fluid-like features required for cell proliferation, migration and dissemination, a process we call unjamming. Here we uncovered that the changes in cell density resulting from the unjamming phenomenon result in mechanical deformations of cells and nuclei that ultimately lead to an alteration of the cell states towards the emergence of malignant features that include epithelial-to-mesenchymal plasticity and chemoresistance (published in 2022 DOI 10.1038/s41563-022-01431-x).
SHAPINCELLFATE teams continue the project, aiming at understanding the mechanisms linked to cell shape and the memory-induced changes.
