When cancer comes calling, normal cells fight back. but how?

Representative image of cancer cells. Photo: NCI/Unsplash


  • When a single cancer cell arises in a group of normal cells, they work together to remove the cancerous cell from the tissue.
  • This removal is well-documented, but scientists still wanted to know the chemical and physical signals that tell normal cells what to do.
  • A team at TIFR Hyderabad conducted a series of tests in which it discovered new, even counterintuitive results to answer this and other questions.
  • The study, which has been praised by independent scientists, adds an “important piece in the puzzle of how” the microenvironment of our cells affects cancers.

Hyderabad: Scientists from the Tata Institute of Basic Research, Hyderabad, have revealed new insights into an important defense mechanism the body uses to respond to early stages of cancer.

The findings are important because they shed light on key concepts that can guide future work to help the body respond better in these early stages, before the cancer progresses.

“This paper is a written example of basic research that can be translated into new ideas and new technologies,” said Tully Dai, a cancer biologist at Savitribhai Full-Bun University. “This should encourage our funding bodies to fund basic research.”

The common metaphor for cancer is the battle: Cancer cells that arise due to genetic mutations quickly defeat normal cells, causing the cancer to spread. Biologists’ name for this process, in which cells compete with each other for space and resources, is straightforward: cell-cell competition.

Scientists consider cell-cell competition to be a primary defense mechanism that protects the body from cancer when the cancer takes root. When a single cancer cell arises in a group of normal cells, they work together to remove the cancerous cell from the tissue. This process is called cell extrusion.

While cell extrusion is well documented, scientists are still searching for answers to many questions. For example, how do normal cells get rid of a cancer cell? What are the chemical and physical signals that tell normal cells what to do?

The team of researchers at TIFR Hyderabad, led by Tamal Das, principal investigator, answered some of these questions in their study published on January 11, 2022.

Das was interested in doing the study because of his long-standing interest in how cells behave collectively in a group. Shilpa b. Puthabragada, a doctoral student with Das and a member of the study, was drawn to the interdisciplinary field of mechanobiology–the study of how physical and mechanical forces affect cellular processes.

epithelial tissue

“Tissue” is the name of the material our bodies are made of. It consists of cells and their products.

The most common tissue in any living organism is the epithelium. It covers the surfaces and cavities of the body, among other things. Examples include the skin and the lining of the gut.

Since about 80% of all cancers are epithelial in origin, Das said Wiring Science that “cancer can be called, in some respects, epithelial tissue disease.”

For researchers interested in studying the collective behaviors of cells, epithelial tissue is a great place to start. Tissue cells are tightly packed, which means that they perform many of their functions together as a group.

Now, these cells are surrounded by the extracellular matrix (ECM). This is a network of proteins, minerals and other macromolecules that support cells in tissues both physically and chemically.

Scientists already know that the ECM changes in many ways in the presence of cancer. One of them is that it becomes Harder. This happens because two components of the ECM – a protein called collagen and a compound called hyaluronic acid – begin to form bonds with each other. Scientists know that there is a positive association between the process of extracorporeal tissue that is more solid and tumor formation, which is the genesis of cancer.

The TIFR team’s question was as follows: If cancer is often a disease of epithelial tissue, then why are carcinomas. From Epithelial tissue so rare?

That is, about 80% of all cancers are epithelial in origin, according to Das. This means that 80% of carcinomas that occur occur in the epithelial tissue. But since mutations that lead to cancer are found everywhere, that’s a total Number The incidence of epithelial cancer should be much higher. But this is not the case.

why?

To get answers, the team investigated Epithelial defense against cancer. The idea is that epithelial tissue, of all tissues, has a built-in defense that pushes newly formed tumor cells backwards and away from invading tissues. One unit in this defense is cell extrusion.

studying

The team members grew epithelial cells in Petri dishes in the lab. Here, they mixed two groups of cells. One population is made up of normal cells and the other is made up of cells genetically modified to become cancerous.

They let the mixed population grow as a single layer – much like how epithelial cells grow in the body – on top of a hydrogel, a highly porous material made mostly of water. (The hydrogel was a proxy for ECM.)

The researchers found that when cells were grown on a less rigid hydrogel, normal cells would extrude cancer cells more efficiently than when the cells were grown on a more rigid hydrogel.

Second, cancer cells that did not sprout on more rigid substrates continued to grow and took up more and more space in the layer — mimicking the way early-stage cancer progresses.

For Das, this was one of the study’s most surprising findings.

He said that, “Because more rigid substrates exert a lot of forces on cells, I had the impression that cell extrusion would work better on more rigid substrates. However, what we found was quite the opposite.”

Gautam I Menon, a mechanical biologist and professor at Ashoka University, Haryana, praised the study for highlighting “one way to understand why conditions such as obesity and aging, which lead to tissue hardening, are associated with an increased risk of cancer.”

He also said that this study reaffirms his belief that “the role of [physical] Forces in a range of biological processes cannot be neglected.”

molecular mechanism

After they discovered that the stiffness of the ECM could affect how well normal cells were able to flush cancer cells out of tissue, Das and his team set out to try to find out exactly how this happened — at the molecular level.

Imagine that each cell is a building. The components of the cell, such as ribosomes, mitochondria, endoplasmic reticulum, etc., are arranged in the rooms on each floor. The walls of this building are the cell’s cytoskeleton: they are made mostly of proteins and help the cell maintain its shape and size.

There are three types of cytoskeleton in cells. One of them is called microfilaments. It is mainly made up of a protein called actin. This actin is bound together using many other proteins, one of which is filamin.

Microscopic view of melanoma cells showing cell nuclei (blue), actin (red), actin regulator (green) and actin-rich structures called podosomes (yellow). Photo: NCI/Unsplash

TIFR researchers found that filamin changes its location within cells in two ways.

First, when a cancer cell and a normal cell come into contact with each other, the researchers found that in the normal cell filamin approached the cell-cell interface, suggesting it has a role to play in cell extrusion.

Second, the situation of the two filamin changed for the worse as the engine control unit became stiffer. This means that for cells grown on a relatively stiffer hydrogel, filamin was found to center around the cell nucleus, rather than moving toward the cell-cell interface.

Based on these findings, the team had an idea: When the ECM hardens, filamin builds up around the nucleus and reduces the amount of filamin at the cell-cell interface. This leads to failure of cell extrusion.

To test their hypothesis, Pothapragada & co. Genetically engineered cells to produce more filamin, growing them as a single layer on a stiffer hydrogel. They found that the cells’ ability to make more filamin allowed them to flush out cancer cells.

This confirmed their prediction that a lack of filamin at the cell-cell interface was responsible for the failure of the cell extrusion process.

Next, they asked: How do the two filamins feel when the engine control unit is stiffer?

In other words, how do physical forces change the outside The cell stimulates the filamin to move inside cell?

Biologists call this mechanical transmissionThe process by which physical signals outside the cell are converted into chemical signals inside.

Confocal micrograph of a cell showing the nucleus (blue), mitochondria (red) and the actin cytoskeleton (green). Photo: NCI/Unsplash

The team found that a protein that binds to filamin, called Cdc42, helped transport filamin to the cell-cell interface, while another protein, called RefilinB, recruited filamin to wrap around the nucleus.

When they inhibited Cdc42 activity by treating cells with chemical inhibitors, they found that even less stiff substrates, filamin can no longer assemble at the cell-cell interface.

Similarly, when they inhibited RefilinB’s activity by genetically modifying the protein, filamin was unable to localize around the nucleus.

Intervene in the fight

At this point, the researchers knew that a more rigid electronic processing unit caused the cell extrusion to fail, and how. Next, they tried to see if they could somehow help the cell extrude the cancer cells even when the ECM was stiffer.

For this, the researchers used cells that had been modified to inhibit the activity of RefilinB. So even as the ECU gets stiffer, its film can’t get lodged around the core. This means that there will be more filamin available at the cell-cell interface.

To the team’s delight, normal cells can effectively extrude cancer cells even on the toughest surfaces.

Nagaraj Balsubramanian, associate professor at the Indian Institute of Science Education and Research, Pune, where he studies how cells attach to the ECM, appreciated the study for adding “an important piece to the puzzle of how the ECM microenvironment affects cancers.”

“The techniques used in the paper are time-consuming and challenging,” said De, a cancer biologist.

Puthabragada said the team was almost ready to report the first draft of the paper when the Indian government imposed a nationwide lockdown in March 2020. So they had to stop their work completely for some time, after which the team had to work in shifts.

When they finally sent the final draft of their paper to a journal that accepted it, its editors allowed the team extra time to answer their queries. This is needed, Puttharagada said, “because the second wave hit us soon after.”

next steps

he said that Wiring Science The team has been studying in parallel what kind of forces act on cancer cells when they are extruded; He said the pressure strength appears to be outstanding. This means that the cancer cells appear compacted. That’s not surprising – but the team needs to know what the pressure does.

The team is collaborating with Max B, a theoretical physicist in the Northeastern University School of Science in Boston, to uncover the source of these forces. Bi models a system based on Das lab results and makes predictions, Das & co. They test it.

The researchers are also trying to replicate their findings in a more physiologically appropriate model system: organelles. An organ is a miniature version of an organ, such as a heart or lung. Memberships are a bridge between in the laboratory Cell culture models and in vivo animal models. For Das’ team, the challenge is culturing the organelles as well as figuring out a way to control ECM stiffness.

Balasubramanyan said Wiring Science He is also interested in knowing whether the response of epithelial cells to changing ECM stiffness has any effects on slow-proliferating rapidly cancers.

Sayantan Datta (they/them) is a transgender science writer, communicator, and journalist. They are currently working with the feminist multimedia science collective TheLifeofScience.com, and they tweet on @queerssprings.

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