Cellular pushing and stretching, a key to the body’s response to processes such as cancer

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Rat lung responding to ventilation with YAP protein staining. Credit: Institute of Bioengineering of Catalonia (IBEC)

From the vocal cords that produce our voice, to the heartbeat, the cells of our body are constantly subjected to mechanical forces that constantly change their response to these stimuli, regulating vital processes in both healthy and healthy individuals. in diseases such as cancer. However, despite their importance, we remain largely unaware of how cells detect and respond to these forces.

Now, an international team co-led by researcher Pere Roca-Cusachs, of the Institute of Bioengineering of Catalonia (IBEC), and Isaac Almendros, researcher at the Center for Biomedical Research in Respiratory Disease Networks (CIBERES) and IDIBAPS, both professors of the Faculty of Medicine and Health Sciences of the University of Barcelona (UB), has shown that what determines the mechanical sensitivity in Barcelona is the speed at which it is applied, that is, the speed with which the force is applied. The document has been published in the prestigious journal Communications on Nature and shows, for the first time in vivo, predictions of the “molecular clutch” model.

These results open the door to a better understanding of how a cancerous tumor proliferates, as well as how the heart, the or the respiratory system responds to the constant variation of forces to which they are repeatedly exposed.

A constant cellular ‘push and pull’

The researchers observed that there are two responses to the force applied to a cell, using state-of-the-art techniques such as atomic force microscopy (AFM) or so-called “optical clamps.”

On the one hand, the , the dense network of fibers (mainly actin), which has, among other things, the function of maintaining the shape and structure of the cell, is strengthened when the cell is subjected to a moderate force. In this sense, the cell is able to detect and respond to the mechanical force and the strengthening of the cytoskeleton leads to a rigidity of the cell and to the location of the YAP protein in the nucleus. When this happens, the YAP protein controls and activates genes related to cancer development.

On the other hand, if the applied force rate is repeatedly applied above a certain value, an inverse effect occurs; the cell no longer perceives the . In other words, instead of making the cytoskeleton and the cell more rigid, a partial decomposition of the cytoskeleton occurs which leads to a softening of the cell.

“Like stretching and shrinking chewing gum, we have subjected cells to different forces in a controlled and precise manner and we have seen that the speed at which the force is applied is of the utmost importance in determining the cellular response.” explains Ion Andreu (IBEC), co-author of the study.

A model corroborated by in vivo experiments

To understand how the strengthening and softening effects of the cytoskeleton are related, the researchers developed a computational model that considers the effect of the progressive application of force on the cytoskeleton and “couplings” (proteins involved in the binding of the cytoskeleton). cell in the substrate, such as talin and integrin). These “couplings” are somewhat similar to the effect of a car’s clutch, by tightening the mechanical connection between the engine and the wheels, which is why the model is known as “molecular clutch”.

The scientists then performed experiments to show that the results observed in individual cells also occur in whole organs in vivo. To do so, the researchers studied the lungs, which naturally experience cyclic mechanical stretching during respiration. Specifically, both lungs were ventilated at different speeds, with one lung filling and emptying more quickly (hyperventilation) and the other slower, maintaining a normal total ventilation rate.

After analyzing and comparing cells from both lungs, they observed that the YAP protein increased its nuclear localization only in hyperventilated lung cells. This increase in YAP in in vivo samples, caused by ‘cell pull-and-pull’, was similar to that found in proliferating cancer tumors.

“Our results demonstrate, at the organ level, the role of the rate of force application in the transduction of the mechanical signal induced by ventilation in the lungs,” says Bryan Falcones (IBEC-UB), co-author of the ‘study.

The paper establishes a mechanism by which cells respond not only to direct forces but also to other passive mechanical stimuli, such as the rigidity of the substrate on which they are located. The results allow us to understand how a priori opposite phenomena, such as strengthening and softening the cytoskeleton, can go hand in hand with the control of cell mechanics and respond specifically to different situations.


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More information:
Ion Andreu et al, The speed of force loading promotes cell mechanosension both through the reinforcement and smoothing of the cytoskeleton, Communications on Nature (2021). DOI: 10.1038 / s41467-021-24383-3

Provided by the Institute of Bioengineering of Catalonia

Citation: Cellular push and pull, a key to the body’s response to processes such as cancer (2021, July 16) retrieved July 16, 2021 at https://medicalxpress.com/news/2021-07- cellular-key-body-response- cancer.html

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