A new study showing how tumour cells behave when surrounded by a disordered microenvironment could help cancer researchers by providing a biophysics model describing how cancers spread within the human body.

Researchers led by Michael Sixt, head of the Cellular Morphodynamics Group and Edouard Hannezo, leader of the Physical Principles in Biological Systems Group both at the Institute of Science and Technology Austria (ISTA), in collaboration with scientists from the UK’s Francis Crick Institute, have constructed a microfluidic chip experiment and associated computer simulation that shows how heterogeneity (disorder) surrounding a tumour can drive metastasis.

Cancers spread when individual cells detach from the tumour cell collective and invade previously healthy tissue. Whether detachment occurs depends on both genetics and the local microenvironment – including blood vessels, immune cells, signalling molecules and connective tissue. To replicate cancer cells squeezing through pores between the fibres of the tissues they are invading, the researchers created forests of pillars mounted on microfluidic devices for tumour cells to squash past.

As detailed in their recent Science Advances paper, the geometry for some forests was a square lattice of 9 µm-diameter pillars evenly spaced with 9 µm gaps between them, while other forests had their pillars arranged in a disorderly pattern created by moving each pillar from its ordered position by a random angle and distance.

“There were no suitable tools for designing mathematically defined disorder. So I had to write completely new software that can define those patterns, and then translate that into designs that can be manufactured [via standard semiconductor lithography techniques] into microfluidic devices,” explains biotech data science consultant Saren Tasciyan, who designed the microfluidic devices as part of his PhD with the Sixt Group.

The team used a combination of fluorescence imaging and light microscopy to track the behaviour of cancer cells – kept alive for up to eight days thanks to cell culture medium – after they were introduced into the centre of each respective pillar forest. These experiments revealed that the tumour cell collective was more likely to break apart when faced with a heterogeneous environment to navigate compared with a more regular geometry.

In the heterogeneous conditions “we found that the first cells detach, exactly as happens in a cancer metastasis,” says Sixt. The team also observed the pillars increasingly rough up the surface of the spreading cell interface, resulting in finger-like protrusions – from whose tips the cells were more likely to detach.

“When the cell interface moves through this landscape the effects accumulate over time,” continues Sixt, who asked his colleague Hannezo to create computer simulations to verify the experimental results, and study the process over longer periods than the cells could survive.

“Each cell was modelled as a bead that moves through an environment,” says Hannezo group postdoc Zuzana Dunajová, a computational scientist specializing in biological physics, who built the model. These beads are attracted to one another, and move through different geometries that mimic those on the microfluidic devices, she explains.

“I kept seeing the same behaviour in my simulations – the beads detached from the collective more often in the disordered environment compared to the ordered. This was very exciting from the physics perspective because it’s not something that we see just in this particular cell type or system, but suggests a more general principle in living, or active systems. The roughness of the cancer-cell invasion actually follows the same kind of universal behaviour as we see in other systems, such as combustion of paper, spreading of fires or drying coffee drops,” enthuses Dunajová.

Next, Sixt – who hopes these insights will help researchers developing new cancer therapies – plans to study whether cell detachment in a disordered microenvironment leads to epigenetic modifications (heritable changes that do not alter the DNA code) and then later on to genetic modifications. “I want to consider whether the detachment process can drive the single cell evolution into something malignant,” Sixt concludes.

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Spirostomum uses a calcium-activated protein network to contract at remarkable speed without conventional muscle fibers. In less than five milliseconds, the aquatic single-celled organism Spirostomum ambiguum can shrink to one quarter of its body length, a movement hundreds of times faster than a human blink. Researchers have now traced that speed to an unusual calcium-activated [...]

The trap lobes of the Venus flytrap – a carnivorous plant – snap shut by the rapid softening of their outer walls. This discovery by researchers in France is at odds with previous hypotheses that the mechanism involves water transport through the lobes.

The Venus flytrap is native to temperate and subtropical wetlands in the eastern US. These habitats are very poor in nutrients, so the plants capture insects and spiders to obtain nitrogen. “[Charles Darwin] was completely amazed by the motion, and he thought that if the plant was moving that fast it was because the plant had muscle,“ says biophysicist Yoël Forterre of Aix-Marseille University. “He thought, ‘OK, if the plant has muscle then it must also have nerves’.” Darwin asked his colleagues, who had recently discovered electrophysiological signals in animals like frogs, to measure the plants, and was proved partially correct: ionic signalling in plant cells was first detected in the Venus flytrap. Nonetheless, plants have no muscles or nerves.

 In 2005, Forterre and colleagues in the UK and US discovered that the trap’s rapid closure is amplified by a “snap-buckling instability”. In the trap’s open state, the two lobes adopt buckled, convex shapes that resist closure. These store elastic energy until a potential barrier is overcome. They then release the energy, suddenly becoming concave and snapping the trap shut in around 0.2 s. The underlying driving force has remained mysterious, however, and the instability makes measurement difficult.

“Many biological and chemical tools are kind of invasive and trigger the plant,” explains Forterre; “It’s not easy to probe the state of the plant before, after and most importantly during the motion.”

Poroelastic limit

One hypothesis is that osmosis causes water to diffuse from one side of the lobe to the other, causing bending. This is the most common driver of motion in plants, but its speed limit can be calculated theoretically from the permeability and elasticity of the host material. To work out whether or not the intrinsic speed of the trap exceeded this “poroelastic limit”, the researchers had to remove the amplificatory effect of the snap-buckling instability.

They devised two ways to do this. First, they cut the trap in several places, allowing it to open and close without storing elastic energy. Second, they clamped traps open between two fixed walls, one equipped with a force sensor. In both cases, they found that the closure timescale – inferred in the case of the trap that did not actually close – was around 4 s. Though much longer than in a trap with a snap-buckling instability, this time would have required water to cross the lobes more than an order of magnitude faster than the porolastic limit. This suggested osmosis could not be responsible.

Another popular hypothesis, first advanced in 1981, is that enlargement and softening of the outer walls drives the lobes into the concave shape. The researchers triggered the trap and probed the pressure of the outer surface with a nano-indenter, confirming that it did indeed decrease. However, this did not affirmatively prove that the material had become more flexible, because an osmotic pressure drop would also cause softening.

Forterre and colleagues used dental impression paste to make moulds of the topography of the cell walls before and after the trap was triggered. “If a balloon becomes softer because you have decreased the pressure, that means it has deflated,” explains Forterre; “If you keep the pressure inside the balloon constant but make the material softer, it will inflate.” The researchers confirmed using microscopy that the cells bulged more after the trap was triggered, showing that the driving force was cell-wall softening, not water movement.

The research is described in Science.

Biologist Anja Geitmann of McGill University in Canada describes the new work as “paradigm changing”. “Usually we always talk about changes in turgor pressure that induce movement,” she says; “Here they show that it’s not a change in turgor pressure but a very rapid change in the mechanics of the primary cell wall. That’s completely new: I know of no other system where this happens on this kind of timescale, and they prove it in very smart and clever ways.”

Plant biologist Daniel Cosgrove of Pennsylvania State University in the US, whose group discovered the proteins that allow cell walls to expand and soften, agrees that the research proves conclusively that osmosis is not the cause of the trap’s closure. “What will complete the story is when there’s a paper out explaining the molecular mechanism of how that cell wall gets softened or loosened in a couple of seconds,” he says.

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Some animals could sense Earth’s magnetic field by using the superparamagnetic properties of white blood cells in their livers, a new interdisciplinary study has revealed. Led by Clivia Lisowski at the University of Bonn, the team’s insights into homing pigeon navigation could help scientists resolve the decades-old mystery of how animals can sense magnetic fields. The research also shines new light on the inner workings of the immune system.

Animals ranging from sharks to bats appear to use Earth’s magnetic field to navigate during long migratory voyages. However, the nature of this magnetoreception is poorly understood.

“How they sense Earth´s magnetic field has been a mystery,” Lisowski explains. “Several hypotheses were suggested, but these have often resulted from laboratory experiments. They were hardly ever done in the field, and so couldn’t explain how migration would work at night or in dark environments.”

In their study, Lisowski’s team investigated the origins of magnetoreception in homing pigeons. These birds are famous for finding their way back home after being released in unfamiliar locations. “We combined expertise from research fields that usually are not intersected, namely immunology, physics and animal behaviour,” Lisowski explains. “[This gave] us a truly interdisciplinary approach to solve the mystery of magnetoreception in homing pigeons.”

Searching for magnetism

As part of this approach, the researchers searched for magnetism in several different tissues of the bird – including the liver, spleen, muscle, and beak. They used vibrating-sample magnetometry (VSM), whereby samples are placed in a constant magnetic field and vibrated up and down. If the sample is magnetic, it will induce an electric field that is proportional to its magnetization.

The team also did field studies of homing pigeon flight patterns and studied the birds’ anatomy. The latter involved using dyes to visualize microscopic structures embedded in tissues along with genomic assays of the tissues.

This combined analysis revealed the presence of superparamagnetic macrophages in homing pigeon livers. Macrophages are specialized white blood cells whose primary function is to engulf and digest pathogens. They are a cornerstone of the immune system. Superparamagnetic means that the macrophages are very easily magnetized.

“The macrophages are superparamagnetic due to their physiological function of degrading old and damaged red blood cells,” Lisowski explains. “They sequester and store the iron from red blood cells as oxide nanoparticles in ferritin proteins.”

Connecting to the brain

Within homing pigeon livers, the researchers found that these macrophages were often in the vicinity of – and sometimes even in direct contact with – nerve fibres in liver tissue. This could allow magnetic information to be passed from macrophages to the brain.

At the atomic level, Lisowski’s team proposes that the effect emerges from unpaired electrons in ferritin proteins, which interact with each other through magnetic dipole–dipole coupling to enhance their magnetic susceptibility. This subatomic effect could in turn explain the distinctive circling behaviour observed in pigeons after they take off. This circling could allow these unpaired electrons to be imprinted with magnetic information, before the birds settle into a more uniform flight.

The research could also improve our understand of the immune system. The team suspects that the sensing abilities imparted by their superparamagnetic properties could enable macrophages to better gauge their surrounding environments: distinguishing between what to fight, and what to tolerate.

“Our finding that the immune system can also sense the Earth´s magnetic field is a completely new layer in this concept of ‘immuno-sensation’, and opens the door to new research,” Lisowski says.

The research is described in Science.

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Bird flocks, bacterial swarms, and even crowds move according to interaction rules that appear to break one of physics’ most fundamental principles: Newton’s law of action and reaction. Birds can see much of what is happening around them, but when flying in a flock, they respond only to birds beside them or ahead of them. [...]