Mechanical mismatch between Ras transformed and untransformed epithelial cells

Gullekson, Corinne; Cojoc, Gheorghe; Schürmann, Mirjam; Guck, Jochen; Pelling, Andrew E.

doi:10.1101/152942

Cited by 6 publications

(11 citation statements)

References 64 publications

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“…In this way, we were able to compare the stiffness of interphase and mitotic cells with the same shape (Figure 3A). Under these conditions, interphase Ras V12 -expressing cells were significantly softer than interphase controls, as previously reported for rounded cells (Gullekson et al, 2017). At the same time, Ras V12 -expressing cells were marginally but significantly stiffer than control cells in mitosis (Figure 3B).…”

Section: Ras Activation Alters Cell Mechanicssupporting

confidence: 86%

Oncogenic Signaling Alters Cell Shape and Mechanics to Facilitate Cell Division under Confinement

et al. 2020

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Section: Ras Activation Alters Cell Mechanicssupporting

confidence: 86%

Oncogenic Signaling Alters Cell Shape and Mechanics to Facilitate Cell Division under Confinement

et al. 2020

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“…In this way, we could directly compare the stiffness of interphase and mitotic cells with the same shape ( Figure 3A). Under these conditions, Ras V12 expressing cells were significantly softer in interphase than controls, as previously reported for rounded cells 22 . At the same time, Ras V12 expressing cells were marginally but significantly stiffer than control cells in mitosis ( Figure 3A).…”

Section: Ras-erk Signaling Alters Cell Contractility In Mitosissupporting

confidence: 86%

“…This is in line with the well-documented role of the Ras-ERK pathway in controlling actin filament organization in interphase to promote cell motility and invasion 27,28 . Ras also affects interphase cell mechanics; inducible activation softens or stiffens cells in a substratedependent manner 22,29 while long-term overexpression softens interphase cells 30 , as we have observed here. Ras also regulates acto-myosin rearrangements at mitotic exit to determine how daughter cells re-spread after division 31 .…”

Section: Discussionsupporting

confidence: 74%

Oncogenic signaling alters cell shape and mechanics to facilitate cell division under confinement

Matthews

Ganguli

Plak

et al. 2019

Preprint

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When cells enter mitosis, they become spherical and mechanically stiffen. We used MCF10A cell lines as a model system in which to investigate the effect of induced oncogene expression on mitotic entry. We find that activation of oncogenic Ras V12 , for as little as five hours, changes the way cells divide. Ras V12 -dependent activation of the MEK-ERK signalling cascade alters acto-myosin contractility to enhance mitotic rounding. Ras V12 also affects cell mechanics, so that Ras V12 expressing cells are softer in interphase but stiffen more upon entry into mitosis. As a consequence, Ras V12 expression augments the ability of cells to round up and divide faithfully when confined underneath a stiff hydrogel. Conversely, inhibition of the Ras-ERK pathway reduces mitotic rounding under confinement, resulting in chromosome segregation defects. These data suggest a novel mechanism by which oncogenic Ras-ERK signalling can aid division in stiff environments like those found in tumours.

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“…Inhibition of myosin-either via ROCK (Y-27632), for which myosin II is a downstream effector, or directly (blebbistatin)-decreased the stiffness and/or increased the relaxation of tumor spheroids. The ROCK inhibitor decreased the elastic modulus of spheroids from both cell lines, which has been observed for other cells and tissues [52,55,73]. Blebbistatin, however, only decreased the elastic modulus of the HCT116 spheroids, not the SUM149PT spheroids.…”

Section: ‫ܧ‬ 1 ⁄supporting

confidence: 67%

“…Cell aggregate stiffness has been linked to (i) actomyosin-generated tension in embryonic tissues and in epithelial sheets as well as to (ii) excessive extracellular matrix deposition and crosslinking in disease processes such as cancer [54][55][56][57][58]. Cells in spheroid culture produce ECM proteins [36,59,60]; however, they are not thought to be rigid and load-bearing [36].…”

Section: Tumor Spheroid Biomechanical Properties Are Products Of Forcmentioning

confidence: 99%

Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint

Kulwatno

Gearhart

Gong

et al. 2020

Preprint

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ABSTRACTTumor emboli – aggregates of tumor cell within vessels – pose a clinical challenge as they are associated with increased metastasis and tumor recurrence. When growing within a vessel, tumor emboli are subject to a unique mechanical constraint provided by the tubular geometry of the vessel. Current models of tumor emboli use unconstrained multicellular tumor spheroids, which neglect this mechanical interplay. Here, we modelled a lymphatic vessel as a 200 μm-diameter channel in either a stiff or soft, bioinert agarose matrix, and we modelled colon or breast cancer tumor emboli with aggregates of HCT116 or SUM149PT cells, respectively. The stiff vessel model constrained the tumor emboli to the cylindrical geometry, which led to continuous growth of the emboli, in contrast to the growth plateau that unconstrained spheroids exhibit. Emboli morphology in the soft vessel model, however, was dependent on the magnitude of mechanical mismatch between the vessel matrix and the cell aggregates. In general, when the elastic modulus of the vessel was greater than the emboli (Eves / Eemb >1), the emboli were constrained to grow within the vessel geometry, and when the elastic modulus of the vessel was less than the emboli (0 < Eves / Eemb < 1), the emboli bulged into the matrix. Inhibitors of myosin-related force generation decreased the elastic modulus and/or increased the stress relaxation of the tumor cell aggregates, effectively increasing the mechanical mismatch. The increased mechanical mismatch after drug treatment was correlated with increased confinement of tumor emboli growth along the vessel, which may translate to increased tumor burden due to the increased tumor volume within the diffusion distance of nutrients and oxygen.INSIGHT BOXThe growth of tumor emboli—aggregates of tumor cells within vessels—is associated with aggressive cancer progression and metastasis. Models of their growth have not taken into account their biomechanical context, where radial expansion is constrained, but lengthwise expansion is free in the vessel. Here, we modelled the vessel geometry with a cylindrical microchannel in a hydrogel. In contrast to unconstrained or fully embedded aggregates, vessel-like constraint promotes growth of emboli in our model. The growth advantage is increased when the matrix is stiffened or actomyosin contractility weakened, both of which effectively increase the magnitude of mechanical constraint. This study sheds light on increased tumor burden in vessel-based growth and indicates a need to study tumor progression in similar environments.

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Mechanical mismatch between Ras transformed and untransformed epithelial cells

Cited by 6 publications

References 64 publications

Oncogenic Signaling Alters Cell Shape and Mechanics to Facilitate Cell Division under Confinement

Oncogenic Signaling Alters Cell Shape and Mechanics to Facilitate Cell Division under Confinement

Oncogenic signaling alters cell shape and mechanics to facilitate cell division under confinement

Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint

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