To understand cancer dynamics, researchers call the cell behavior 'coiling’

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Time-lapse imaging of a mouse DRG myelinating culture shows the initial connection between a Schwann cell (green) and a thin process that wraps around the axon (red). Arrows indicate clear spiral turns during rotation. Time interval between images is 1 hour. Images are 3D rendered using Zen 2012 (Carl Zeiss) to better emphasize the complex configuration. Scale bar is 20 μm, and timestamp format is hh:mm. debt: Natural communication (2023) DOI: 10.1038/s41467-023-41273-y

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Time-lapse imaging of a mouse DRG myelinating culture shows the initial connection between a Schwann cell (green) and a thin process that wraps around the axon (red). Arrows indicate clear spiral turns during rotation. Time interval between images is 1 hour. Images are 3D rendered using Zen 2012 (Carl Zeiss) to better emphasize the complex configuration. Scale bar is 20 μm, and timestamp format is hh:mm. debt: Natural communication (2023) DOI: 10.1038/s41467-023-41273-y

In any fight, knowing your opponent is key to conducting a defense. The fight to stop cancer or speed up wound healing is no exception. Research teams at Virginia Tech and Israel’s Weizmann Institute, along with partners around the world, are pursuing a deeper understanding of how cells move and spread.

At Virginia Tech Professor Amrinder Nine creates nanoscale suspension bridges to study cell migration. Professor Nir Gove at the Weizmann Institute is developing a theoretical and computational framework for how cells migrate on curved surfaces. Their collaborative study combines cutting-edge experiments and theory to investigate cell „coiling” in filaments. Natural communication.

This study follows Previous research Partnering government and Nine to explore the inner dynamics of cancer. In that work, Nain and his colleagues from Virginia Tech, Japan and Israel studied how a cell’s biology affects the movement of brain cancer cells.

That work produced many new discoveries, but chemistry and biology alone did not provide a complete picture. Since a holistic view of cellular behavior is needed to understand how to stop cancer in its tracks, the team shifted from studying the cell’s interior to its exterior, observing how it interacts with its environment.

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Expanding the team for new research

Nain and Virginia Tech colleague Bahareh Behkam previously identified a cell behavior called coiling, in which a cell migrates by wrapping itself around a fiber axis. They found that spiral was more abundant in cancer-infiltrating cells than in their non-tumorigenic counterparts. Knowing this, they began to understand the fundamental energy principles governing that spiral behavior.

Again needing the government’s expertise, the team began a new collaborative study with the Israel team, with the aim of discovering how a cell moves using its protrusions, or arm-like structures that extend out from the front of a cell’s smooth body.

Nain and his collaborators knew that these arms not only allow the cell to move, but also sense its environment and pull itself forward. The trick is to observe them in 3D at sufficient resolution. Virginia Tech team member Cristian Hernandez-Padilla devised imaging techniques to capture fiber networks and coil phenomena. Nain then contacted Hari Shroff and Harshad Vishwasrao at the National Institutes of Health (NIH) about using their lattice-light sheet advanced microscope.


Cristian Hernandez-Padilla analyzes cells with a microscope in Amrinder Nine’s lab. Credit: Cristian Hernandez-Padilla.

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Cristian Hernandez-Padilla analyzes cells with a microscope in Amrinder Nine’s lab. Credit: Cristian Hernandez-Padilla.

„We were challenged to determine whether the spiral could be clearly seen in 3D for detailed measurements,” Nine said. „All it took was a cold email to Harry at NIH, and he was very receptive. We were thrilled that Christian’s imaging data was tricked out.

In addition to the NIH, the team also reached out to Professor Konstantinos Constantopoulos at Johns Hopkins University to develop the specific cell lines used in the study; Professor Ales Iglic at the University of Ljubljana, Slovenia, for computational modeling; and Professor Elier Beels at the Weizmann Institute of Science for demonstrating coiling in vivo.

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Understanding cell migration requires understanding how cells wrap around fibrous cords—suspension bridges that eventually move. Nine’s expertise includes the development of nanoscale cellular suspensions. Compared to the flat topography of a Petri dish, these filaments are much closer to the topography of living tissue. By partnering with other experts, the team sets out to explain how cells move within a body, which could lead to new strategies to stop cancer cells or speed up wound healing.

A Twisted Grip: Work from Blacksburg

To propel itself, a cell’s jelly-like body first forms tentacle-like protrusions. These cellular arms can grasp objects by twisting around fibers in the tissue around them. But this behavior has rarely been studied before.

„Recent imaging studies inside the body show that cancer cells move along individual filaments and move through heterogeneous fibrous structures by reaching and grasping the filaments,” Nine said. „We combined our experiments with Nirin’s computational models to understand the dynamics of coiling. This had not been attempted before and was a challenge for our teams.”

The coil team studied suspended filaments of various diameters, including flat ribbons pioneered in the Behcom lab. The researchers found that when a cell settles onto a fiber, its tentacle wraps around the fiber a few times, giving the cell a firm grip. Hernández-Padilla performed imaging at NIH and developed a framework to measure 3D spiral events from the massive data recorded.

Scroll: Work from Israel

In Israel, postdoctoral fellow Rajkumar Sadhu developed a theoretical model that describes how a cell acquires its shape and moves when external forces act on its membrane. The government’s panel found that energy reduction was a key driver. A membrane tries to be as flat as possible, avoiding sharp corners that require more energy to navigate.

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Complex coil-like patterns result from protein complexes that bend and bend the membrane as they follow their shape. Curved proteins attach to the cytoskeleton, which gives the cell its shape. The cytoskeleton grows and pushes outward during cellular movement, driving protrusions.

These forces arising from energy conservation and cytoskeleton dynamics are responsible for coiling. The model correctly predicts that coiling stops when the fiber has sharp corners, as in flat ribbons.

Collaboration is important in biology

Although this energy balance between movement and cell biology happens in very small ways, it has enormous implications for the future. Understanding how cells interact with their environment opens the door to understanding cell migration during development, disease, and repair biology.

In addition to the project’s scientific advances, the government commented on the value of this work to the joint venture.

„This collaboration has already produced many publications and demonstrates how science is done today through collaboration between people from different countries, continents and ethnic and national backgrounds,” he said. „Beyond passion and love for science, the liberal principles of freedom, human rights, and mutual respect and solidarity among all people unite us.”

More information:
Raj Kumar Sadhu et al., Experimental and theoretical model for the origin of coiling of cellular protrusions around filaments, Natural communication (2023) DOI: 10.1038/s41467-023-41273-y

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