image: Dr. Joan Massagu
Credit: Memorial Sloan Kettering Cancer Center
Deaths from cancer have fallen dramatically. They’ve dropped by 34% over the past three decades — largely thanks to better treatments, earlier detection, and fewer people smoking. But cancer metastasis remains a stubborn threat.
Metastasis is the name for cancer that has spread from an initial, or “primary” tumor, to other parts of the body. It’s also called stage 4 cancer.
The vast majority of deaths caused by cancer — as many as 9 in 10 — are caused not by an initial tumor, but rather by the impacts of metastasis.
At the same time, metastasis remains poorly understood relative to its importance. Its biology is complex, and it can take a long time to develop, making it challenging and costly to study both in the lab and in people.
“Unlike primary tumors, metastasis is not generally driven by genetic mutations — that is, by changes in the DNA that disrupt the normal function of genes,” says Joan Massagué, PhD, a world-renowned metastasis researcher and Chief Scientific Officer at Memorial Sloan Kettering Cancer Center (MSK). “Metastasis is initiated and sustained by self-renewing cancer cells that act like stem cells, and which have the capacity to hide from our immune defenders for month, years, even decades — until the conditions are ripe to generate a new tumor.”
Over the past few years, MSK researchers have learned a lot about the nuances of metastasis — and these insights will help guide future treatments, he adds.
Earlier this year, Dr. Massagué presented recent findings from his lab to doctors and scientists from around the globe at one of the premier cancer research conferences, the American Associate of Cancer Research (AACR) Annual Meeting.
Here, he shares four of those new insights into how cancer spreads:
Metastatic Cancer Cells Are Time Travelers
So, what does it mean to say that metastasis-initiating cells are like stem cells?
It means that these cancer cells can endlessly divide and produce diverse cell types, similar to stem cells.
At the very earliest stages of human development, our cells are in a flexible state that can give rise to all the different specialized cells our body will need: heart cells, bone cells, skin cells, and so forth. But over time, as our cells start to organize themselves into tissues and organs, they get more specialized and less flexible. For example, blood cell “progenitors” can make red blood cells, white blood cells, and platelets — but not lung cells.
Metastatic cancer cells are able to break the rules, however, to undo that increasing specialization to gain access to genetic programs that are normally locked down after the earliest stages of human development.
“Essentially, they travel back in time to an earlier stage of life,” says Dr. Massagué, who also serves as Director of the Sloan Kettering Institute and heads MSK’s Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center.
This increased flexibility — which scientists call “plasticity” — gives metastatic cells the ability to adapt to a variety of environments and conditions throughout the body, as well as to develop resistance to our best treatments.
“In some ways, metastatic cancer cells are like teenagers, trying out many identities to find the one that works best for them,” he adds.
Dr. Massagué’s lab, in collaboration with the lab of MSK computational biologist Dana Pe’er, PhD, published findings in Nature Medicine showing that in lung cancer, primary tumors contain cell types associated with lung repair, but metastatic lung cancer cells — those that had spread to other parts of the body — reverted to more primitive cell states mimicking early lung development.
This understanding presents opportunities to target cancer cells’ ability to enter these earlier developmental states, as well as to target those states directly, Dr. Massagué notes.
Metastatic Cells Play Cat and Mouse With the Immune System
Rather than focusing on how metastatic cells adapt differently to locations throughout the body — the liver, the brain, the bones — Dr. Massagué’s lab has sought to understand fundamental properties shared by all metastatic cells.
“We reasoned that the place to look for this was the aspect of metastasis that was the least well understood and investigated by the smallest number of labs — and that is dormancy,” he says.
Cancer cells break away from primary tumors all the time. Most of these are hunted down and eliminated by the immune system or succumb to the generally unwelcoming environment of the human body. These cancer cells face physical barriers to accessing the highway of the bloodstream, differing levels of nutrients and oxygen that can exhaust them, as well as the hurdle of finding new tissue conducive to their growth.
“Metastasis is a war of attrition,” he says. “Many cells try, most die.”
To be successful, then, these cells must not only be able to go dormant — to stop dividing and hide out in the body, biding their time for more favorable conditions — but also to exit dormancy and begin proliferating again.
“What are these cells? How do they live? Where do they live? How do they deal with immune defenders and other aspects of the host’s body that threaten them?” Dr. Massagué muses. “Remember, these are individual cells or small clusters of cells that are not protected by the type of environment that primary tumors make for themselves to suppress the immune system’s attack.”
To answer these questions, the lab developed models of dormant metastatic cells from both human tumors and mouse models of lung cancer.
One of the interesting things they discovered is that these dormant cells would occasionally wake up and start to grow new tumors.
“We’re talking about in one or two mice out of 10 or 20,” he says.
But when the researchers used antibodies to deplete immune defenders in the mice, “there is very rapid, multi-organ metastatic outbreak.”
What this shows is that while these cells want to proliferate and start new tumors, when they try, the immune system will usually detect and eliminate them.
So, the researchers’ thought, if one could find a way to wake these cells up, that would help the immune system find them and kill them off.
And that’s exactly what the lab found in a study that was published in Nature: They identified a cell signaling pathway called STING as a key player in this process. In the dormant stage, STING activity is low — and the dormant cells excel at hiding out from immune defenders. But moving out of the dormant stage and into an awakened, proliferative stage, the metastatic cells start to have increased STING activity. This makes them more vulnerable to attack by the immune system.
Then, cells that survive this bottleneck to generate larger clusters, called macrometastastes, again show reduced STING levels, which makes them more resistant to the immune system.
“This means that these tumor cells will be recognized differently by the immune system at different stages of metastasis development,” Dr. Massagué says. “Using STING activators in conjunction with that window of increased STING activity in the reawakened cancer cells could be an opportunity to help the body’s immune defenders destroy them.”
Different Tumor Types Use Different Strategies for Colonizing the Same Organ
It’s not just that cancer cells are able to adapt to the unique environments in different parts of the body as they spread — whether the lungs, the brain, or the bones. Different types of cancer use different strategies for colonizing the same organ, MSK scientists have demonstrated.
In a study published in Cancer Cell, the Massagué Lab showed that two major types of breast cancer — triple-negative breast cancer and HER2-positive breast cancer — employ distinct strategies when spreading to the brain.
Triple-negative cancers, for example, tend to spread out in sheaths around blood capillaries that infiltrate the surrounding tissue, leaving the boundary between the tumor and healthy tissue less defined. HER2-positive cancers, on the other hand, tend to form compact tumor spheroids that are more segregated and defined.
By illuminating the distinctive strategies and spatial organization employed by different cancer subtypes, the researchers hope to help doctors to better treat or prevent metastases by being able to more preciscific to each type, Dr. Massagué says.
Metastatic Cells’ Ability To Shape-Shift Also Helps Them To Survive
Moreover, the ability to change shape also helps protect metastatic cells from the immune system. During dormancy, these cancer cells lose proteins in their cytoskeleton, giving them a more relaxed, round shape.
“Using an atomic force microscope, we can see that surface tension in these cells is highest in the spindle shape and lowest when they are round,” Dr. Massagué says. “When they are round, they have much lower surface tension and it’s harder for the immune cells to attack them and pop them, like a balloon.”
The lab further identified a key player in this shape-shifting ability — a protein called gelsolin. Removing gelsolin in laboratory models allowed the immune cells to better eliminate the cancer cells. Their findings were published as a pre-print on bioRxiv, as well as being presented at AACR.
“So this represents another mechanism that allows metastatic cells to evade the immune system that we could potentially target to prevent cancer from spreading,” Dr. Massagué says.
Discoveries are ’Heartening’
Taken together, the discoveries being made at MSK and by other researchers around the globe are heartening, he adds.
“Metastasis used to be an automatic death sentence, but that is no longer the case,” he says. “In some cases, it is now curable with immunotherapy, and for many cancers it is becoming more controllable. We are probably never going to eliminate it — but we are moving closer and closer to being able to prevent it in some cases, and to manage it the same way we manage other chronic diseases.”