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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Research shows how physical cues drive cell migration, cancer metastasis, and treatment

Cancer cells are a product of their environment. The surrounding cells, extracellular matrix, and other features influence disease progression and spread of cancer cells to other parts of the body. Chemical cues like the presence of nutrients and oxygen have been studied for decades, but more recently, researchers have turned their attention to equally important physical cues.

New research on the tumor mechanical microenvironment will be presented at the 2020 American Physical Society March Meeting in Denver. Highlights include a study that looks at how the anisotropy of the extracellular matrix affects cancer cell migration, a novel optical tweezer-based tool that probes mechanical cues, and a model to find the best place within a tumor to inject a chemotherapy drug.

Mechanical cues drive metastasis

Oregon State University researcher Bo Sun will present his findings on the complex interactions between cancer cell migration and the extracellular matrix, a 3D network of collagen, proteins, and other molecules that support the surrounding cells. Specifically, he will discuss the anisotropy of the extracellular matrix, and how a particular alignment of collagen fibers can create a cancer cell superhighway of sorts.

For most research in the field so far, a dominant paradigm is that rigidity of the tissue environment is the dominant factor that guides cell migration. The cell wants to move to a more rigid region compared to a soft region. We're seeing that a different type of physical property, anisotropy of the environment, is more efficient in terms of guiding cell migration."    Bo Sun, Oregon State University researcher

For instance, collagen fibers aligned circumferentially around the tumor causes the cancer cells to become trapped by this alignment, whereas fibers arranged radially provide a frictionless highway for cells to migrate outward. Studying the way cells move in their environment--and what factors drive that movement--has implications for understanding how cancer cells infiltrate new areas of the body.

Probing tissues with optical tweezers

Biophysicist Kandice Tanner has repurposed a tool to measure the mechanical cues that may influence how tumor cells disseminate to different organs. The optical tweezer-based technique can probe the physical properties of cells in living animals with microscale resolution.

"Previously, characterization of mechanical properties of tissues, cells, and extracellular matrix hydrogels were mainly obtained using bulk rheological or nanometer scale techniques such as atomic force microscopy and primarily for in vitro systems," said Tanner, an investigator at the National Cancer Institute, part of the National Institutes of Health. "These techniques are useful to assess material properties but do not possess the resolution that is needed to resolve length scales that are compatible with the micron-size protrusions used by cells to respond to external cues."

Tanner and her colleagues employed the technique to measure the viscoelastic properties of tissue in living zebrafish and 3D culture models of breast cancer progression. For the latter project, they used optical trap-based active microrheology to map internal cellular and external extracellular matrix mechanics with near simultaneity. They found that, unlike healthy cells, breast tumor cells do not match their mechanical properties to the surrounding microenvironment.

As cancer cells migrate from their original primary tumor, they encounter many physical cues before establishing new lesions in different organs such as the patient's bones, brain, liver, or lungs," said Tanner. "We believe that by decoding the role of the physical cues, we can understand why some tumor cells are able to colonize one organ versus the other."

Shapeshifting cells

While the extracellular matrix simulated in lab experiments is almost purely elastic--it bounces back to its original form once a stress is removed--the scaffolding in the brain, liver, and other tissues is not. In these regions, the extracellular matrix exhibits both viscous and elastic characteristics. Harvard researcher Anupam Gupta will present his research on how viscoelastic properties of the extracellular matrix can transform normal cells into cancer cells.

Gupta and his colleagues have observed that increasing the fluidic nature of the extracellular matrix causes normal breast cells to lose their spherical shape, form a rough interface, and develop fingers. Based on these results, they created a mathematical model of the cell mechanics that shows finger formation stops with increasing viscosity or elasticity.

Modeling cancer drug response

Cancer treatment relies heavily on trial and error, which can lead to unnecessary toxicity and cost. Models that predict how a cancer drug will diffuse throughout the tumor offer a possible solution for oncologists. Aminur Rahman develops these kinds of mechanistic models of drug response as a method for oncologists to choose the most effective treatment before administering any medication.

"Our mechanistic models are able to produce dose-response curves that oncologists would see from cell line and drug data pairs," said Rahman, a post-doctoral researcher at Texas Tech University. "We realized that perhaps this research could be used for computer-aided treatment strategies."

He will present the results of multiple projects in a poster presentation. The first investigates a model of drug distribution after injection directly into a solid tumor and its effect on cancer cell death. While the model assumes the tumor is spherical and homogeneous, brain tumors in particular tend to be highly inhomogeneous and anisotropic. The second study develops a more sophisticated computational model for inhomogeneous-anisotropic drug diffusion using real-world diffusion tensor MRI data.

"Because of the tumor's inhomogeneity and anisotropy, the center might not be the best place to inject drugs," said Rahman. "We looked at different injection sites, and it was not necessary the center that would do the trick. In such cases, having a model would help an oncologist know where to inject the drug."

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Elderly cancer survivors face risk of brain metastasis

Elderly survivors of breast cancer, lung cancer, and melanoma face the risk of brain metastasis later in life, claim researchers.

Brain metastasis is cancer that spread to the brain from other body parts and therefore considered a secondary brain tumour.

“As cancer treatments have gotten better and more people are surviving a primary cancer diagnosis, it’s important to study secondary cancers, including metastasis to the brain. With an ageing U.S. population, the number of people with brain metastasis is increasing, although sometimes that metastasis does not occur until many years after the initial cancer diagnosis,” co-author of the study.

“As people are living longer after an initial cancer diagnosis, their ‘time at risk’ for metastasis is going up. In addition, the majority of primary cancer diagnoses have no standard of care for brain metastasis screening,” co-author added.

The researchers linked data on brain metastases to investigate rates of brain metastasis in elderly patients.

Then they calculated the incidence proportion, the ratio of brain metastases counts to the total number of cases, for each primary cancer.

The highest rates of metastasis were in small-cell and non-small-cell lung carcinoma, compared with adenocarcinoma, a more common type of lung cancer.

The authors said that the results of the study could help clinicians better understand patients’ risk for brain metastasis and could potentially influence screening and surveillance practices.

“Brain metastases are detected with MRI, which is very expensive. An improved understanding of who is likely to develop a brain metastasis could help determine who should get an MRI,” the author said.

The author added that more targeted surveillance could potentially help physicians detect metastases at early stages. If we can identify brain metastases earlier in their progression, that could allow for earlier treatment and improved outcomes for these patients.

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