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Ben-Gurion University and Weizmann Researchers Shed New Light on Wave Motion on Cellular Membranes that Could Have Implications for Cancer Detection and Treatment

19/06/2017

 

BGU and Weizmann Institute of Science researchers have disproved an old model of how actin filaments in cells generate waves while offering a distinct framework that goes beyond the basic understanding of functionality and offers new strategies that might eventually be relevant to cancer detection and treatment. 

Their research was published today in Nature Communications, which is one of the top three most important journals for multi-disciplinary research such as this one, which combined mathematics, biophysics and experimental biology.

Actin filaments are one of the fundamental components of the soft and dynamic skeleton of cells and also play a key role in the reshaping of cell morphologies and cellular motility. The formation of actin filaments manifests in visible cup-shaped ruffles (waves) on the surface and throughout the cell, a behavior that is also known as macropinocytosis, whereby cells produce vesicles that are absorbed into the cell. According to current understandings, such circular waves have a two-fold purpose: to take up large molecules (e.g., nutrients) that the cell needs, but cannot acquire through its ion channels, and to “reset” the cell by disordering the actin infrastructure, i.e., an efficient softening mechanism of the cytoskeleton. The waves also concentrate membrane receptors into the vesicles, allowing cells to respond to external chemical signals. 

Researchers believed until now that the waves were to be attributed to a pulse-like motion similar to the electrical pulses (action potentials) in nerves. However, Dr. Arik Yochelis (BGU), Prof. Nir Gov (Weizmann) and their postdoctoral fellow Dr. Erik Bernitt (Germany) discovered by carefully revisiting these experimentally observed waves that the mathematical description of the pulse assumption mechanism did not fit. Instead, these membrane ruffles belong to a distinct class of generic dynamic behavior: wave-fronts, the wave serves as a propagating wall connecting high and low actin concentrations. They built a robust model that not only reproduces the wave behavior but also qualitatively predicted new dynamic behavior that, surprisingly, has also been found in experiments. Thus their approach opens up new possibilities for many future applications, including cancer research. 

Previous studies in cancer research have implied that deviation from the regular wave dynamics correlates with promotion of cancerous phenotypes, i.e., in cases where these actin-driven waves get damaged or their dynamics are suppressed. In addition, wave-mediated macropinocytosis is an important mechanism of nutrient uptake and receptor recycling in tumor cells, and therefore understanding it better could shed light on its role in cancer cell migration. 

“Now that we have a much clearer understanding of these waves, if we can control their dynamics, then theoretically we could assist in preventing and/or identifying pathways toward and about cancer cells that up to now were overlooked,” say Yochelis and Gov.   

Dr. Erik Bernitt was a visitor at the Weizmann Institute of Science during this collaborative project. Another co-author is Prof. Hans-Günther Döbereiner of Bremen University, who was Dr. Bernitt’s Ph.D. supervisor, and in whose lab the experiments were conducted.

The study received funding from the Adelis Foundation, Ministry of National Infrastructures, Energy and Water Resources of Israel, and the German Academic Exchange Service. 

“Fronts and waves of actin polymerization in a bistability-based mechanism of circular dorsal ruffles”

Erik Bernitt, Hans-Günther Döbereiner, Nir S. Gov & Arik Yochelis ​


Figure 1.jpg  

Figure 1 | Characteristics of CDRs. (a) Time-lapse sequence showing the typical course of a spontaneously formed CDR (scale bar: 25 mm). The white arrow indicates the initiation of the CDR and the red arrow the macropinosomes (appearing as white spots) formed on CDR collapse. 

(b) Living cell stained for f-actin with a close-up view on a CDR wavefront showing its sub-structure of dynamic actin clusters (scale bars: full image 25 mm, close-up 5 mm). 

(c) Kymographs along red lines in normal (n) and tangential (t) direction to the CDR in b, highlighting the rapid actin turnover within CDR wavefronts. 

(d) Actin organization of a cell exhibiting two​ CDRs imaged with confocal fluorescence microscopy in two different z-positions. 

(e) Close-up view of the vertically integrated intensity of the region of interest highlighted with a white rectangle in d.

(f) Profile of fluorescence intensity sampled along a cut through the wavefront (white line in (e), length: 25 mm) showing the state of wavefront exterior (P 0) and wavefront interior (P 1 þ ).

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