Octopus-like tentacles help cancer cells invade the body

With help from the best tweezers in the world a team of researchers from the University of Copenhagen has shed new light on a fundamental mechanism in all living cells that helps them explore their surroundings and even invade tissue. Their discovery could have implications for research into cancer, neurological disorders and much else.

Using octopus-like tentacles, a cell pushes toward its target, a bacterium, like a predator tracking down its prey. The scene could be playing out in a nature programme. Instead the pursuit is being observed at the nano-scale through a microscope at the University of Copenhagen's Niels Bohr Institute. The microscope recording shows a human immune cell pursuing and then devouring a bacterium.

With their new study, a team of Danish researchers has added to the world's understanding of how cells use octopus-like tentacles called filopodia to move around in our bodies. This discovery about how cells move had never been addressed. The study is being published today in the journal, Nature Communications.

"While the cell doesn't have eyes or a sense of smell, its surface is equipped with ultra-slim filopodia that resemble entangled octopus tentacles. These filopodia help a cell move towards a bacterium, and at the same time, act as sensory feelers that identify the bacterium as a prey," explains Associate Professor Poul Martin Bendix, head of the laboratory for experimental biophysics at the Niels Bohr Institute.

The discovery is not that filopodia act as sensory devices -- which was already well established -- but rather about how they can rotate and behave mechanically, which helps a cell move, as when a cancer cell invades new tissue.

"Obviously, our results are of interest to cancer researchers. Cancer cells are noted for their being highly invasive. And, it is reasonable to believe that they are especially dependent on the efficacy of their filopodia, in terms of examining their surroundings and facilitating their spread. So, it's conceivable that by finding ways of inhibiting the filopodia of cancer cells, cancer growth can be stalled," explains Associate Professor Poul Martin Bendix.

For this reason, researchers from the Danish Cancer Society Research Center are a part of the team behind the discovery. Among other things, the cancer researchers are interested in whether switching off the production of certain proteins can inhibit the transport mechanisms which are important for the filopodia of cancer cells.

The cell's engine and cutting torch

According to Poul Martin Bendix, the mechanical function of filopodia can be compared to a rubber band. Untwisted, a rubber band has no power. But if you twist it, it contracts. This combination of twisting and contraction helps a cell move directionally and makes the filopodia very flexible.

"They're able to bend -- twist, if you will -- in a way that allows them to explore the entire space around the cell, and they can even penetrate tissues in their environment," says lead author, Natascha Leijnse.

The mechanism discovered by the Danish researchers appears to be found in all living cells. Besides cancer cells, it is also relevant to study the importance of filopodia in other types of cells, such as embryonic stem cells and brain cells, which are highly dependent on filopodia for their development.

Studying cells with the best tweezers in the world

The project involved interdisciplinary collaboration at the Niels Bohr Institute, where Associate Professor Amin Doostmohammadi, who heads a research group that simulates biologically active materials, contributed with the modelling of filopodia behaviour.

"It is very interesting that Amin Doostmohammadi could simulate the mechanical movements we witnessed through the microscope, completely independent of chemical and biological details," explains Poul Martin Bendix.

The main reason that the team succeeded in being the first to describe the mechanical behaviour of filopodia is that NBI has unique equipment for this type of experiment, as well as skilled researchers with tremendous experience working with optical tweezers. When an object is extraordinarily small, holding onto it mechanically becomes impossible. However, it can be held and moved using a laser beam with a wavelength carefully calibrated to the object being studied. This is called an optical tweezers.

"At NBI, we have some of the world's best optical tweezers for biomechanical studies. The experiments require the use of several optical tweezers and the simultaneous deployment of ultra-fine microscopy," explains Poul Martin Bendix.

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Touch and taste? It's all in the tentacles

 

Suction cups on octopus tentacles

Octopuses have captured the human imagination for centuries, inspiring sagas of sea monsters from Scandinavian kraken legends to TV's "Voyage to the Bottom of the Sea" and, most recently, Netflix's less-threatening "My Octopus Teacher." With their eight suction-cup covered tentacles, their very appearance is unique, and their ability to use those appendages to touch and taste while foraging further sets them apart.

In fact, scientists have wondered for decades how those arms, or more specifically the suction cups on them, do their work, prompting a number of experiments into the biomechanics. But very few have studied what is happening on a molecular level. In a new report, Harvard researchers got a glimpse into how the nervous system in the octopus' arms (which operate largely independently from its centralized brain) manage this feat.

The work published Thursday in Cell.

The scientists identified a novel family of sensors in the first layer of cells inside the suction cups that have adapted to react and detect molecules that don't dissolve well in water. The research suggests these sensors, called chemotactile receptors, use these molecules to help the animal figure out what it's touching and whether that object is prey.

"We think because the molecules do not solubilize well, they could, for instance, be found on the surface of octopuses' prey and [whatever the animals touch]," said Nicholas Bellono, an assistant professor of molecular and cellular biology and the study's senior author. "So, when the octopus touches a rock versus a crab, now its arm knows, 'OK, I'm touching a crab [because] I know there's not only touch but there's also this sort of taste.'"

In addition, scientists found diversity in what the receptors responded to and the signals they then transmitted to the cell and nervous systems.

"We think that this is important because it could facilitate complexity in what the octopus senses and also how it can process a range of signals using its semi-autonomous arm nervous system to produce complex behaviors," Bellono said.

The scientists believe this research can help uncover similar receptor systems in other cephalopods, the invertebrate family that also includes squids and cuttlefish. The hope is to determine how these systems work on a molecular level and answer some relatively unexplored questions about how these creatures' capabilities evolved to suit their environment.

"Not much is known about marine chemotactile behavior and with this receptor family as a model system, we can now study which signals are important for the animal and how they can be encoded," said Lena van Giesen, a postdoctoral fellow in the Bellono Lab and lead author of the paper. "These insights into protein evolution and signal coding go far beyond just cephalopods."

Along with Giesen, other co-authors from the lab include Peter B. Kilian, an animal technician, and Corey A.H. Allard, a postdoctoral fellow.

"The strategies they have evolved in order to solve problems in their environment are unique to them and that inspires a great deal of interest from both scientists and non-scientists alike," Kilian said. "People are drawn to octopuses and other cephalopods because they are wildly different from most other animals."

The team set out to uncover how the receptors are able to sense chemicals and detect signals in what they touch, like a tentacle around a snail, to help them make choices.

Octopus arms are distinct and complex. About two-thirds of an octopus's neurons are located in their arms. Because the arms operate partially independently from the brain, if one is severed it can still reach for, identify, and grasp items.

The team started by identifying which cells in the suckers actually do the detecting. After isolating and cloning the touch and chemical receptors, they inserted them in frog eggs and in human cell lines to study their function in isolation. Nothing like these receptors exists in frog or human cells, so the cells act essentially like closed vessels for the study of these receptors.

The researchers then exposed those cells to molecules such as extracts from octopus prey and others items to which these receptors are known to react. Some test subjects were water-soluble, like salts, sugars, amino acids; others do not dissolve well and are not typically considered of interest by aquatic animals. Surprisingly, only the poorly soluble molecules activated the receptors.

Researchers then went back to the octopuses in their lab to see whether they too responded to those molecules by putting those same extracts on the floors of their tanks. They found the only odorants the octopuses receptors responded to were a non-dissolving class of naturally occurring chemicals known as terpenoid molecules.

"[The octopus] was highly responsive to only the part of the floor that had the molecule infused," Bellono said. This led the researchers to believe that the receptors they identified pick up on these types of molecules and help the octopus distinguish what it's touching. "With the semi-autonomous nervous system, it can quickly make this decision: 'Do I contract and grab this crab or keep searching?'"

While the study provides a molecular explanation for this aquatic touch-taste sensation in octopuses through their chemotactile receptors, the researchers suggest further study is needed, given that a great number of unknown natural compounds could also stimulate these receptors to mediate complex behaviors.

"We're now trying to look at other natural molecules that these animals might detect," Bellono said.

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