EMT induces cell-cycle-dependent changes of Rho GTPases and downstream effectors
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Abstract
Epithelial-mesenchymal transition (EMT) is a key cellular transformation for many physiological and pathological processes ranging from cancer over wound healing to embryogenesis. Changes in cell migration, cell morphology and cellular contractility were identified as hallmarks of EMT. These cellular properties are known to be tightly regulated by the actin cytoskeleton. EMT-induced changes of actin-cytoskeletal regulation were demonstrated by previous reports of cell-cycle-dependent changes of actin cortex mechanics in conjunction with characteristic modifications of cortex-associated f-actin and myosin. However, at the current state, the changes of upstream actomyosin signalling that lead to corresponding mechanical and compositional changes of the cortex are not well understood. In this work, we show in breast epithelial cancer cells MCF-7 that EMT results in characteristic changes of the cortical signalling of Rho-GTPases Rac1, RhoA and RhoC and downstream actin regulators cofilin, mDia1 and Arp2/3. In the light of our findings, we propose that cell-cycle-dependent EMT-induced changes in cortical mechanics rely on two hitherto unappreciated signalling paths - i) a cell-cycle-dependent interaction between Rac1 and RhoC and ii) an inhibitory effect of Arp2/3 activity on cortical association of myosin II.
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"do you mean that after a cell undergoes EMT and adopts a mesenchymal phenotype that it then has an increased likelihood to proliferate?" That's what I meant - yes.
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thanks for replying! Am I just thinking about this from a single cell perspective vs. population? When you say that cells undergoing EMT do so with enhanced proliferation, do you mean that after a cell undergoes EMT and adopts a mesenchymal phenotype that it then has an increased likelihood to proliferate? I was thinking about it more along the lines of the process of EMT and the potential cell cycle checkpoints that might be associated with that cell behavior and the accompanying cell shape changes going from an epithelial layer to a mesenchymal state (at the level of single cells).
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In our experiments with metastatic cancer cells so far, EMT was always going together with enhanced proliferation. Particularly in 'healthy' cell lines (or benign phenotype cancer cell lines) such as HaCaT cells or MCF10A, it was frequently found that EMT reduces proliferation in 2D culture . See also https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202001276 and https://pubs.rsc.org/en/content/articlehtml/2022/sm/d2sm00159d
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interphase
Have you thought about how different interphase states (G1/S/G2) might affect the underlying biology? For example, it could be that cells localize proteins in unique ways in G1 or G2 and that my taking your measurements en masse, you might miss out on the subtleties.
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EMT was reported to be connected to enhanced cell migration and cell proliferation in metastatic cancer cells
there is a really interesting literature "Go vs. Grow" that suggests that when cells adopt invasive/migratory phenotypes, such as undergoing EMT, that they arrest in the cell cycle. This creates a dichotomy between proliferation and invasion, suggesting that from a cell biological perspective, these cell behaviors may be mutually exclusive, at least in some contexts.
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we worked with rounded, non-adherent cells since this has the advantage that cell shapes are spherical in both epithelial and EMT-transformed conditions with a largely uniform actin cortex. In this way, a meaningful comparative analysis of cortical protein association between epithelial and the mesenchymal-like cells becomes possible.
I appreciate trying to generate equivalent conditions to do your comparison, but I am confused as to how rounded cells are equivalent to cells that have adopted a mesenchymal migratory/invasive morphology? Specifically because cells undergoing EMT need to undergo massive polarization changes from their epithelial state.
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