Cancer cells become more aggressive when migrating through small spaces

The findings of new research suggest that squeezing through tight spaces makes cancer cells more aggressive and helps them evade cell death.

 

The findings, published in 'eLife', reveal how mechanical stress makes cancer cells more likely to spread, or metastasis.

 

While metastasis is the cause of most cancer deaths, there are currently no available cures. However, the new results may help scientists develop novel approaches to treat or prevent metastasis. It can be a tight squeeze for cancer cells to escape their tumour or enter tiny blood vessels, called capillaries, to spread through the body. The cells must collapse and change their shape to do this, in a process called confined migration. As they spread, the cells must also avoid detection and destruction by the immune system.

 

"Mechanical stress can cause cancer cell mutations, as well as an uncontrolled increase in cell numbers and greater tissue invasion," explains first author Deborah Fanfone, Postdoctoral Fellow at the Cancer Research Center of Lyon, France. "We wanted to know if the mechanical stress of confined migration makes cancer cells more likely to metastasise, and how this happens."

 

To answer these questions, Fanfone and colleagues forced human breast cancer cells through a membrane with tiny, three-micrometer-sized holes to simulate a confined migration environment. After just one passage through the membrane, they found that the cells became more mobile and resistant to anoikis - a form of programmed cell death that occurs when cells become detached from the surrounding network of proteins and other molecules that support them (the extracellular matrix).

The cells were also able to escape destruction by immune natural killer cells.

 

Further experiments showed that increased expression of inhibitory-of-apoptosis proteins (IAPs) increased the resistance of cancer cells to anoikis. Treating the cancer cells with a new type of cancer drug called a SMAC mimetic, which degrades IAPs, removed this protection.

 

The team then studied how breast cancer cells that had undergone confined migration behave when administered to immune-suppressed mice. They found these mice developed more lung metastases than mice that were administered with breast cancer cells that had not been exposed to confined migration.

 

"By mimicking confined migration, we've been able to explore its multifaceted effects on cancer aggressiveness," says senior author Gabriel Ichim, who leads the Cancer Cell Death team at the Cancer Research Center of Lyon. "We've shown how the process boosts survival in cancer cells and makes them more prone to forming deadly metastases."

 

The authors add that these results may lead to additional studies of potential metastasis treatments, such as therapies that soften tumours to reduce mechanical stress on cancer cells, or that block IAPs. These include SMAC mimetics, which are currently being tested in clinical trials as a possible new treatment approach.

 

 

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Discovery about how cancer cells evade immune defences inspires new treatment approach

A recent discovery about the process of evasion by cancer cells has led researchers towards a new approach to treat the disease.

Cancer cells are known for spreading genetic chaos. As cancer cells divide, DNA segments and even whole chromosomes can be duplicated, mutated, or lost altogether. This is called chromosomal instability, and scientists at Memorial Sloan Kettering have learned that it is associated with cancer's aggressiveness.

The more unstable chromosomes are, the more likely that bits of DNA from these chromosomes will end up where they don't belong: outside of a cell's central nucleus and floating in the cytoplasm.

Cells interpret these rogue bits of DNA as evidence of viral invaders, which sets off their internal alarm bells and leads to inflammation. Immune cells travel to the site of the tumour and churn out defensive chemicals. A mystery has been why this immune reaction, triggered by the cancer cells, does not spell their downfall.

"The elephant in the room is that we didn't really understand how cancer cells were able to survive and thrive in this inflammatory environment," said Samuel Bakhoum, a physician-scientist at MSK and a member of the Human Oncology and Pathogenesis Program.

According to the new study from Dr. Bakhoum's lab in the journal Cancer Discovery, the reason has to do, in part, with a molecule sitting on the outside of the cancer cells that destroys the warning signals before they ever reach neighbouring immune cells.

The findings help to explain why some tumours do not respond to immunotherapy, and -- equally important -- suggest ways to sensitize them to immunotherapy.

Detecting Dangerous DNA

The warning system Dr. Bakhoum studies is called cGAS-STING. When DNA from a virus (or an unstable cancer chromosome) lands in a cell's cytoplasm, cGAS binds to it, forming a compound molecule called cGAMP, which serves as a warning signal. Inside the cell, this warning signal activates an immune response called STING, which addresses the immediate problem of a potential viral invader.

In addition, much of the cGAMP also travel outside the cell where it serves as a warning signal to neighbouring immune cells. It activates their STING pathway and unleashes an immune attack against the virally infected cell.

Previous work from the Bakhoum lab had shown that cGAS-STING signalling inside of cancer cells causes them to adopt features of immune cells -- in particular, the capacity to crawl and migrate -- which aids their ability to metastasize. This provided part of the answer to the question of how cancer cells survive inflammation and aid metastasis in the process.

The new research shows how the cancer cells cope with the warning signals that activated cGAS-STING releases into the environment. A scissor-like protein shreds the signals, providing a second way the cells can thwart the threat of immune destruction.

The scissor-like protein that coats cancer cells is called ENPP1. When cGAMP finds its way outside the cell, ENPP1 chops it up and prevents the signal from reaching immune cells. At the same time, this chopping releases an immune-suppressing molecule called adenosine, which also quells inflammation.

Through a battery of experiments conducted in mouse models of breast, lung, and colorectal cancers, Dr. Bakhoum and his colleagues showed that ENPP1 acts like a control switch for immune suppression and metastasis. Turning it on suppresses immune responses and increases metastasis; turning it off enables immune responses and reduces metastasis.

The scientists also looked at ENPP1 in samples of human cancers. ENPP1 expression correlated with both increased metastasis and resistance to immunotherapy.

Empowering Immunotherapy

From a treatment perspective, perhaps the most notable finding of the study is that flipping the ENPP1 switch off could increase the sensitivity of several different cancer types to immunotherapy drugs called checkpoint inhibitors. The researchers showed that this approach was effective in mouse models of cancer.

Several companies -- including one that Dr. Bakhoum and colleagues founded -- are now developing drugs to inhibit ENPP1 on cancer cells.

Dr. Bakhoum says it's fortunate that ENPP1 is located on the surface of cancer cells since this makes it an easier target for drugs designed to block it.

It's also relatively specific. Since most other tissues in a healthy individual are not inflamed, drugs targeting ENPP1 primarily affect cancer.

Finally, targeting ENPP1 undercuts cancer in two separate ways: "You're simultaneously increasing cGAMP levels outside the cancer cells, which activates STING in neighbouring immune cells, while you're also preventing the production of the immune-suppressive adenosine. So, you're hitting two birds with one stone," Dr. Bakhoum explains.

The pace of the research has been incredibly fast, he says. "One of the things I would be really proud of is if this research ends up helping patients soon, given that we only just started this work in 2018."

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