Biology subjects

Matic Vignjevic, D.

Publications and source records attributed to Matic Vignjevic, D..

5 recordsLinked to original sources

bioRxiv2023

Aging and freezing of active nematic dynamics of cancer-associated fibroblasts by fibronectin matrix remodeling

Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types in tumor stroma. Exhibiting an elongated morphology, CAFs align with each other, closely resembling nematic ordering in liquid crystal physics. CAFs play a pivotal role in the genesis and remodeling of the extracellular matrix (ECM), with ECM proteins, especially fibronectin, reciprocally modulating CAF alignment and coherence. Yet, the intricate feedback loops between fibronectin deposition and CAF structuring remain largely unexplored. Here, we combined CAF live imaging, traction force microscopy, ECM microfabrication, and theoretical modeling to assess how the ECM influences the dynamics of nematically ordered CAFs. We found that CAFs dynamically orchestrate a fibronectin network that mirrors their nematic ordering. Over time, this passive nematic ordering of fibronectin, in turn, steers CAF rearrangement. Contrary to most cellular systems, where defects remain dynamic at a steady state, the ECM/CAF interplay profoundly alters the behavior of both CAF and ECM nematics, leading to aging-massive slowdown, and even freezing of defect dynamics. This results in a CAFs capsule where aligned areas and defects are spatially and temporally fixed, yet active, exerting forces at the substate and transmitting forces between cells. Functionally, while defects may be permissive, it is the fibronectin loss-induced fluidization of the CAF capsule that critically undermines its barrier function.

cell biology↗

bioRxiv2023

Mechanical regulation of cell fate transitions underlying colorectal cancer metastasis formation

Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site are devoid of Lgr5 expression. It is currently unknown how CRC cell fate transitions are regulated during the metastatic process and how tumor cells give rise to metastatic lesions despite being Lgr5neg. Here, we show that the reprogramming of disseminating CRC cells is driven by mechanical interactions with the Collagen I-rich interstitial matrix. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a fetal-like state. The fetal-like state is maintained after reaching the blood circulation and promotes metastasis-initiation of disseminated CRC cells in the liver. Our findings indicate a key contribution of mechanical signals in controlling cell fate transitions that underlie the metastatic potential of CRC, involving an interplay between different mechanosensitive mechanisms.

cancer biology↗

bioRxiv2022

Mechanical forces across compartments coordinate cell shape and fate transitions to generate tissue architecture

Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. An excellent paradigm to understand the coupling of these processes is mammalian hair follicle development, initiated by the formation of an epithelial invagination - termed placode - that coincides with the emergence of a designated hair follicle stem cell population. The mechanisms directing the deformation of the epithelium, cell state transitions, and physical compartmentalization of the placode are unknown. Here, we identify a key role for coordinated mechanical forces stemming from contractile, proliferative, and proteolytic activities across the epithelial and mesenchymal compartments in generating the placode structure. A ring of fibroblast cells gradually wraps around the placode cells to generate centripetal contractile forces, which in collaboration with polarized epithelial myosin activity promote elongation and local tissue thickening. These mechanical stresses further enhance and compartmentalize Sox9 expression to promote stem cell positioning. Subsequently, proteolytic remodeling locally softens the basement membrane to facilitate release of pressure on the placode, enabling localized cell divisions, tissue fluidification, and epithelial invagination into the underlying mesenchyme. Together, our experiments and modeling identify dynamic cell shape transformations and tissue-scale mechanical co-operation as key factors for orchestrating organ formation.

developmental biology↗

bioRxiv2022

Fibroblasts generate topographical cues that steer cancer cell migration

Fibroblasts play a fundamental role in tumor development. Among other functions, they regulate cancer cells migration through rearranging the extracellular matrix, secreting soluble factors and establishing direct physical contacts with cancer cells. Here, we report that migrating fibroblasts deposit on the substrate a network of tubular structures that serves as guidance cue for cancer cell migration. Such membranous tubular network, hereafter called tracks, is stably anchored to the substrate in a {beta}5 integrin-dependent manner. We found that cancer cells specifically adhere to tracks by using clathrin-coated structures that pinch and engulf tracks. Tracks represent thus a spatial memory of fibroblast migration paths that is read and erased by cancer cells directionally migrating along them. We propose that fibroblast tracks represent a topography-based intercellular communication system capable of steering cancer cells migration. TEASERThe migration path of fibroblasts is marked by tubules that act as railways to direct following cancer cell migration.

cancer biology↗

bioRxiv2021

Evolution of a confluent gut epithelium under cyclic stretching

The progress of food in the gastrointestinal (GI) tract is driven by a peristaltic motion generated by the muscle belt surrounding the GI tract. In turn, the response of the intestinal epithelial cells to the peristaltic stresses affects the dynamics of the epithelial structure. In this work, we study the effect of cyclic stretching (0.125 Hz, 10% strain) on the spatial organization of the intestinal epithelium using intestinal cells deposited on a flat elastomeric substrate to mimic the peristaltic motion in vitro. A confluent monolayer of Caco-2 cells is grown on a PDMS chip to probe the morphological and orientational response of the tissue to cyclic stretching. The PDMS chips are either covalently or non-covalently coated with laminin to recapitulate the basement membrane. We observe a significant orientational response where the cells rearrange their long axes perpendicular to the stretching direction for both coating conditions. The experiment is modeled by a vertex model where the cells store elastic energy with varying strain and effectively have a rotational diffusive motion through rearrangements of their shapes. The model also predicts a transition between the perpendicular orientation and orientation at an oblique angle determined by the level of the cell elastic anisotropy. It provides a general framework to study cell response and relaxation dynamics under cyclic stretching across different cell types. We also discuss potential relevance of peristalsis in determining planar cell polarity in 3D architectures.

biophysics↗