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Oncogenic signaling alters cell shape and mechanics to facilitate cell division under confinement
Preprint posted on March 09, 2019 https://www.biorxiv.org/content/10.1101/571885v1
Categories: cancer biology, cell biology
Context:
Most animal cells undergo different degrees of rounding up when entering mitosis both in cell culture and in vivo (Cadart et al. 2014). This is important for accurate spindle positioning and metaphase plate formation (Lancaster and Baum, 2014). For cells to survive, they need to maintain division in the complex environments. In order to do so, cells require contractility of acto-myosin cytoskeleton (Champion et al. 2017). To understand how mitosis successfully occurs in different extra-cellular environments, it is imperative to study the role of contractility, the upstream regulators of contractility and mechanics during this process.
Major findings:
To understand how cancer cells, regulate contractility to successfully divide in different environments, the authors transformed epithelial cells (MCF10A) by over-expressing a single oncogene, Rasv12. This is a simple system to look at the role of upstream signaling in regulating mitotic rounding without the caveats of having extra chromosome numbers or centrosome aberrations. The authors find that inducible Ras activation signals through the MEK/ERK pathway and enhances cell rounding during mitosis. They also show that Ras activation alters Rho-based contractility during mitosis. To understand how this transformation effects the mechanics of dividing cells, they measure the stiffness of the cells sitting on the surface by using atomic force microscopy (AFM) and real time deformability cytometry (RT-DC), a high- throughput method to measure the stiffness of cells in suspension. Interestingly, Ras activation leads to softer cells during interphase but stiffer cells during metaphase. The role of Ras activation in enhancing mitotic rounding becomes more obvious under stiff confinement. The authors show that increase in contractility is required for the push to successfully divide and reduce mitotic defects under confinement.
What I liked about the preprint
It is interesting for me that small term activation of Ras is enough for changing the mechanics of the cell undergoing mitosis. Authors show the importance of oncogenic signaling that could provide cancer cells with a capacity to undergo mitosis successfully in confinements like tumor spheroids and cells undergoing EMT. Therefore, this is a study that shows another example of temporal regulation of signaling controlling mechanics and cellular geometry.
What’s next and my questions to the author:
I would be curious to know how the interphase cells with Ras activation show reduced stiffness when attached to the surface and even when in suspension. According to previous studies, I could find that cells are only softer in loosely adhered cells (Gullekson et al. 2017). Ras/ERK activation clearly regulates cortical contractility during mitosis, my view would be that this happens via changes in the cortical thickness that would maintain cortical tension. This could be measured by STORM imaging during various stages of mitosis. It is still not clear to me how Ras activation, even before cells enter interphase, regulate stiffness temporally. One way I could see how cancer cells could achieve this would be regulating mitotic kinases like CDK1, which would then feed on to Rho signaling. A previous study showed that oncogenic Ras suppresses CDK1 expression (Huang et al. 2013). It will be interesting to see how CDK1, ROCK and ECT2 (RhoA-GEF) localization changes with progression of mitosis.
References
Huang, Tun-Lan, Jerry P. Pian, and Bin-Tao Pan. 2013. “Oncogenic Ras Suppresses Cdk1 in a Complex Manner during the Incubation of Activated Xenopus Egg Extracts.” Archives of Biochemistry and Biophysics. https://doi.org/10.1016/j.abb.2013.01.006.
Posted on: 1st May 2019 , updated on: 3rd May 2019
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Ankita Jha
Authors response
Thank you for your summary and great suggestions.
One of the most exciting findings of this work for us is the discovery that even short-term activation of an oncogene (only 5 hours) affects how cells control their shape during mitosis. Understanding the molecular mechanism behind these changes is one of our key aims in following up this study. We think it is likely to involve multiple Ras-induced changes to downstream signaling pathways, cell morphology and actin organization in interphase and during mitotic rounding. Ras-induced alterations to Cdk1 activation during mitotic entry may play a part in these changes, as you suggest. We will certainly include this hypothesis in our investigations.
We find that Ras-expressing cells are softer than controls in interphase and therefore increase their stiffness more when they enter mitosis. This allows them to round up better under confinement. We do not yet understand how Ras functions to alter cell mechanics, but this is something we plan to address in our future work. Your suggested experiment of using STORM imaging to measure cortical thickness is a great one – it would be interesting to know whether Ras alters intrinsic features of the cortex such as thickness or actin filament organization and how this differs between interphase and mitosis. It would also be very interesting to study these effects in different contexts – for example, while single rounded cells soften following Ras activation, cells in an epithelium have been shown to stiffen (Gulleckson et al 2017).