The spread of cancer from a primary tumor to another place in the body, called metastasis, remains one of the greatest challenges in cancer treatment and is responsible for most cancer-related deaths.
“Cancer cells that have moved to another part of the body can stay dormant for years after the original tumor has been treated,” explains Crick group leader Ilaria Malanchi, who leads a lab studying how cancer cells interact with the rest of the body. “It’s a worrying period for people, as they don’t know if these metastatic cells will reactivate, leading to a relapse.”
Breast cancer cells often spread to the bone marrow, where they can lie dormant for years within the tissue that normally supports the production of new blood cells. These disseminated cancer cells enter a “sleeping” state, which helps them evade the immune system and resist chemotherapy. What causes them to “wake up” is not only a key issue in cancer biology but also a huge challenge to study.
“We can’t wait five years to see if dormant cancer cells reactivate in mice, as this exceeds their life span,” Malanchi explains. “We’ve known for a long time that we need to think creatively about a new model.”
Thinking outside of the bone
In research published in Cell Reports, Stefania di Blasio and Tatiana Rizou in Malanchi’s team, building on previous work from Laurie Gay, established a way to model dormant metastatic breast cancer cells in mice.
They engineered an “extramedullary bone model,” a section of bone tissue that is grown from skeletal stem cells and sits underneath the skin. Like natural bones, the replica bone contains all the bone marrow cells needed to produce new blood cells and can respond to the body’s inflammatory signals to increase their production.
“We then added cells from a mouse mammary tumor onto the replica bone,” explains Malanchi. “Most entered a dormant state, with only sporadic replication activity.”
Now that they had a model that recreated “sleeping” metastatic cells in the bone, the team could test what might shake them out of dormancy.
Modeling metastatic triggers
Injuries to the bone like fractures can lead to the growth of metastatic cancer cells hosted in the bone marrow, but the team wanted to establish if more indirect insults throughout the body, such as those caused by injury or infections, could also kick-start tumor development.
“We induced intestinal colitis—inflammation in the gut—in the mice with the extramedullary bone hosting dormant metastatic cells. Because the replica bone responds to the immune system, gut inflammation triggered a rapid production of immune cells from the bone,” Malanchi explains.
The bone marrow environment needs to remodel to boost production of new immune cells, and it turned out that this change had a profound effect on the dormant cancer cells. More cancer cells started replicating, which increased the risk of a tumor forming.
By analyzing which genes were being switched on in the bone cells and the cancer cells, the team showed that a molecule that stimulates cell growth, HMGB2, increased as immune cell production surged, but also promoted the awakening of dormant cancer cells.
“Even without inflammation elsewhere in the body, just the increased HMGB2 in the artificial bone was enough to stimulate more cancer cells to activate,” Malanchi says. “We also analyzed bone samples from people with breast or prostate cancer—HMGB2 was present where there were actively dividing cancer cells.
“All of these findings suggest that boosting immune cell production in the bone, as part of a normal response to inflammation, comes at the cost of disrupting tumor dormancy, tipping the balance toward reactivation and metastatic growth.”
Monitoring infections
Malanchi is keen to emphasize that it’s not an all-or-nothing game, where inflammation will always trigger relapse. “We think it’s a piecemeal situation where each systemic change increases the chance of more metastatic cells waking up each time,” she says.
The research suggests that monitoring people in this critical period after remission for infections, inflammation or injury anywhere in the body may indicate whether dormant cells are more likely to reactivate.
“Once cancer cells are actively replicating, they can respond to chemotherapy, so understanding developments affecting the bone marrow could lead to early intervention,” Malanchi concludes.
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