Cancer Cells Sense Fibers by Coiling on them in a Curvature-Dependent Manner

Mukherjee, Apratim; Behkam, Bahareh; Nain, Amrinder S.

doi:10.1016/j.isci.2019.08.023

Cited by 27 publications

(32 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, the utility of lateral protrusions remains poorly understood, as classic 2D culturing methods limit the formation of lateral protrusions, while 3D gels lack the homogeneity and topographic patterning needed to study the role of fiber geometry on protrusion frequency, morphology, and dynamics. To partially remedy this, we recently used orthogonal arrangement of fibers of mismatched fiber diameters to constrain cell migration along large diameter fibers while studying lateral protrusions of various shapes and sizes on smaller diameter fibers 30,31 . We observed the protrusions formed in an integrin-dependent manner on small diameter fibers, and notably suspended flat ribbons of equivalent widths did not capture protrusive sensitivity to curvature 30 .…”

mentioning

confidence: 99%

Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction

et al. 2020

Self Cite

View full text Add to dashboard Cite

Aligned extracellular matrix fibers enable fibroblasts to undergo myofibroblastic activation and achieve elongated shapes. Activated fibroblasts are able to contract, perpetuating the alignment of these fibers. This poorly understood feedback process is critical in chronic fibrosis conditions, including cancer. Here, using fiber networks that serve as force sensors, we identify "3D perpendicular lateral protrusions" (3D-PLPs) that evolve from lateral cell extensions named twines. Twines originate from stratification of cyclic-actin waves traversing the cell and swing freely in 3D to engage neighboring fibers. Once engaged, a lamellum forms and extends multiple secondary twines, which fill in to form a sheet-like PLP, in a forceentailing process that transitions focal adhesions to activated (i.e., pathological) 3Dadhesions. The specific morphology of PLPs enables cells to increase contractility and force on parallel fibers. Controlling geometry of extracellular networks confirms that anisotropic fibrous environments support 3D-PLP formation and function, suggesting an explanation for cancer-associated desmoplastic expansion.

show abstract

mentioning

confidence: 99%

Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both 2D substrates and micropatterned stripes provide controllable and reproducible environments, but neither fully models the details of in vivo native cellular environments, which consist of extracellular matrices of fibrous proteins, with these fibers having different radii. Our earlier in vitro recapitulation of the effects of fiber curvature showed that both protrusive and migratory behavior is sensitive to fiber diameter [19][20][21] . Furthermore, we have shown that suspended flat 2D ribbons do not capture the protrusive behavior observed on suspended round fibers 19 , thus, we wanted to inquire if the CIL rules developed on 1D collision and 2D assays extend to contextually relevant fibrous environments.…”

Section: Introductionmentioning

confidence: 99%

Rules of contact inhibition of locomotion for cells on suspended nanofibers

Singh

Pagulayan

Camley

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Contact inhibition of locomotion (CIL), in which cells repolarize and move away from contact, is now established as a fundamental driving force in development, repair, and disease biology. Much of what we know of CIL stems from studies on two-dimensional (2D) substrates that do not provide an essential biophysical cue—the curvature of extracellular matrix fibers. We discover rules controlling outcomes of cell–cell collisions on suspended nanofibers and show them to be profoundly different from the stereotyped CIL behavior on 2D substrates. Two approaching cells attached to a single fiber do not repolarize upon contact but rather usually migrate past one another. Fiber geometry modulates this behavior; when cells attach to two fibers, reducing their freedom to reorient, only one cell repolarizes on contact, leading to the cell pair migrating as a single unit. CIL outcomes also change when one cell has recently divided and moves with high speed—cells more frequently walk past each other. Our computational model of CIL in fiber geometries reproduces the core qualitative results of the experiments robustly to model parameters. Our model shows that the increased speed of postdivision cells may be sufficient to explain their increased walk-past rate. We also identify cell–cell adhesion as a key mediator of collision outcomes. Our results suggest that characterizing cell–cell interactions on flat substrates, channels, or micropatterns is not sufficient to predict interactions in a matrix—the geometry of the fiber can generate entirely new behaviors.

show abstract

“…Studies by the Yamada group have demonstrated how single-cell behavior in 3D microenvironments can be recapitulated through the use of narrow 1D microprinted lines of varying widths (1-40 µm) [32] . Microprinted lines are essentially 2D surfaces, and in our study, we inquired if suspended 1D fibrillar architecture of precisely controlled fiber diameters (150-6000 nm) and interfiber spacing regulated nuclear responses of uniaxial spread cells, as we have previously shown protrusive, contractile, and migratory behavior of uniaxial cells to be sensitive to fiber curvature and spacing [33][34][35][36][37][38][39] . In this study, we chose nucleus rupture and the spatial localization of YAP/TAZ as two markers of nuclear response to changes in fiber curvatures.…”

Section: Introductionmentioning

confidence: 99%

Sculpting rupture-free nuclear shapes in fibrous environments

Jana

Tran

Gill

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Cytoskeleton-mediated force transmission regulates nucleus morphology. How nuclei shaping occurs in fibrous in vivo environments remains poorly understood. Here a suspended nanofiber assay of precisely-tunable (nm-μm) diameters is used to quantify nucleus plasticity in fibrous environments mimicking the natural extracellular matrix. In contrast to the apical cap over the nucleus in cells on 2-dimensional surfaces, the cellular cytoskeleton of cells on fibers displays a uniform actin network caging the nucleus. The role of contractility-driven caging in sculpting nuclear shapes is investigated as cells spread on aligned single fibers, doublets, and multiple fibers of varying diameters. Cell contractility increases with fiber diameter due to increased focal adhesion clustering and density of actin stress fibers, which correlates with increased mechanosensitive transcription factor YAP translocation to the nucleus. Unexpectedly, large- and small-diameter fiber combinations lead to teardrop-shaped nuclei due to stress-fiber anisotropy across the cell. As cells spread on fibers, diameter-dependent invaginations that run the nucleus’s length are formed at contact sites. The deepest and sharpest invaginations are insufficient to trigger nucleus rupture, often observed in 2D or confined systems. Overall, we describe the unknown adaptability of nuclei to fibrous environments and resultant sculpting of the nucleus shapes, with pathophysiological implications.

show abstract

Cancer Cells Sense Fibers by Coiling on them in a Curvature-Dependent Manner

Cited by 27 publications

References 52 publications

Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction

Force-exerting perpendicular lateral protrusions in fibroblastic cell contraction

Rules of contact inhibition of locomotion for cells on suspended nanofibers

Sculpting rupture-free nuclear shapes in fibrous environments

Contact Info

Product

Resources

About