Biology subjects

Zhovmer, A. S.

Publications and source records attributed to Zhovmer, A. S..

4 recordsLinked to original sources

bioRxiv2023

Septins Enable T Cell Contact Guidance via Amoeboid-Mesenchymal Switch

Lymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septins GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues. SIGNIFICANCE STATEMENTDeciphering mechanisms of guided lymphocyte migration paves the way towards effective immunotherapies for the extracellular matrix-rich tissues, such as solid tumors. Here we demonstrate that T cell septins GTPase activity regulates both actomyosin and microtubules, alternately enhancing either of these two major motor systems. Surprisingly, the suppression of septin GTPase activity also induces a highly guided integrin-dependent mesenchymal-like migration directed by the extracellular matrix proteins. The phenomenon of guided mesenchymal-like migration of T cells relies on the microtubules and microtubule-based dynein motors that are responsible for the force generation, powering guided T cell motility. This finding opens a new perspective for future studies of septin GTPases in a context of the optimisation of T cell-based immunotherapies for the solid tissues.

cell biology↗

bioRxiv2023

Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer

Metastasis is a principal cause of death in cancer patients, which remains an unresolved fundamental and clinical problem. Conventionally, metastatic dissemination is linked to the actomyosin-driven cell locomotion. However, locomotion of cancer cells often does not strictly line up with the measured actomyosin forces. Here, we identify a complementary mechanism of metastatic locomotion powered by the dynein-generated forces. These forces that arise within a non-stretchable microtubule network drive persistent contact guidance of migrating cancer cells along the biomimetic collagen fibers. We also show that dynein-powered locomotion becomes indispensable during invasive 3D migration within a tissue-like luminal network between spatially confining hydrogel microspheres. Our results indicate that the complementary contractile system of dynein motors and microtubules is always necessary and in certain instances completely sufficient for dissemination of metastatic breast cancer cells. These findings advance fundamental understanding of cell locomotion mechanisms and expand the spectrum of clinical targets against metastasis.

cell biology↗

bioRxiv2022

Septin-Mediated Mechanobiological Reprogramming of T Cell Transmigration and 3D Motility

The all-terrain motility of lymphocytes in tissues and tissue-like gels is best described as amoeboid motility. For amoeboid motility, lymphocytes do not require specific biochemical or structural modifications to the surrounding extracellular matrix. Instead, they rely on changing shape and steric interactions with the microenvironment. However, the exact mechanism of amoeboid motility remains elusive. Here we report that septins shape T cells for amoeboid motility. Specifically, septins form F-actin and alpha-actinin-rich cortical rings at the sites of cortex-indenting collisions of T cells with the extracellular matrix. Cortical rings compartmentalize cells into chains of spherical segments that are spatially conformed to the available lumens, forming transient hourglass-shaped steric locks onto the surrounding collagen fibers. The steric lock facilitates pressure-driven peristaltic propulsion of cytosolic content by individually contracting cell segments. Our results demonstrate that septins provide microenvironment-guided partitioning of actomyosin contractility and steric pivots for amoeboid motility of T cells in tissue-like microenvironments. GLOSSARYO_LISteric interactions - interactions by the means of their spatial collision dependent on objects shapes. C_LIO_LISteric guidance - cell navigation within crowded 3D environments, determined by the available passages around and between steric hindrances. C_LIO_LIPeristaltic treadmilling - locomotion mode by the means of a repeated sequence of polarized cell cortex extension, stabilization, and retraction, accompanied by translocation of nucleus and cytoplasm via circumferential cortex contractility. C_LI Significance StatementT cells can be highly motile, searching for cognate antigens or better yet targets in chimeric antigen receptor therapy settings. However, mechanisms of motility remain elusive for T cells migrating in structurally and biochemically diverse tissues. Here we address one pivotal question of basic and clinical immunology - How T cells achieve the all-terrain motility? Here we decipher and report septin-based T cell motility in a 3D tissue-like environment. Specifically, we show that septins facilitate cell morphological responsiveness to the steric obstacles, i.e., collagen fiber-wise partitioning of actomyosin cortex contractility and cell-obstacle steric interactions. These responses coordinate peristaltic propulsion of the lymphocytes cytosolic content along its individually contracting cell segments, forming the obstacle-avoiding motility, i.e., circumnavigation, shared across various tested lymphocytes.

biophysics↗

bioRxiv2021

Mechanical counterbalance of kinesin and dynein motors in microtubular network regulates cell mechanics, 3D architecture, and mechanosensing

Microtubules (MTs) and MT motor proteins form active 3D networks made of unstretchable cables with rod-like bending mechanics that provide cells with a dynamically changing structural scaffold. In this study, we report an antagonistic mechanical balance within the dynein-kinesin microtubular motor system. Dynein activity drives microtubular network inward compaction, while isolated activity of kinesins bundles and expands MTs into giant circular bands that deform the cell cortex into discoids. Furthermore, we show that dyneins recruit MTs to sites of cell adhesion increasing topographic contact guidance of cells, while kinesins antagonize it via retraction of MTs from sites of cell adhesion. Actin-to-microtubules translocation of septin-9 enhances kinesins-MTs interactions, outbalances activity of kinesins over dyneins and induces discoid architecture of cells. These orthogonal mechanisms of MT network reorganization highlight the existence of an intricate mechanical balance between motor activities of kinesins and dyneins that controls cell 3D architecture, mechanics, and cell-microenvironment interactions.

biophysics↗