Researchers at the Francis Crick Institute have discovered that inflammation from infections or injuries elsewhere in the body can reactivate dormant breast cancer cells hidden in bone marrow. Published in Cell Reports, the study reveals how immune responses trigger the growth molecule HMGB2, breaking tumor dormancy and increasing relapse risks.
Metastasis remains one of the greatest challenges in cancer treatment and is responsible for most cancer-related deaths, according to the research team. Breast cancer cells frequently spread to the bone marrow, where they can lie dormant for years within tissue that normally supports new blood cells. These disseminated cancer cells enter a sleeping state that helps them evade the immune system and resist chemotherapy, leaving patients in a prolonged period of uncertainty about whether a relapse might occur.
Modeling Metastatic Dormancy in Mice
Studying this process has long presented a major hurdle because researchers cannot wait five years to see if dormant cells reactivate within a mouse’s natural lifespan. To overcome this, Crick group leader Ilaria Malanchi and her lab — building on previous work from Laurie Gay — engineered an extramedullary bone model. Team members Stefania di Blasio and Tatiana Rizou developed sections of bone tissue grown from skeletal stem cells that sit underneath the skin.
These replica bones contain all the bone marrow cells needed to produce new blood cells and respond to inflammatory signals just like natural bones. When researchers added cells from a mouse mammary tumor onto the replica bone, most entered a dormant state characterized by only sporadic replication activity, creating a reliable platform to test potential triggers.
How Intestinal Colitis Triggers Cell Awakening
While bone injuries such as fractures can lead to the growth of hosted metastatic cancer cells, the team investigated whether more indirect insults throughout the body could also kickstart tumor development. By inducing intestinal colitis in mice that hosted dormant metastatic cells in their extramedullary bone models, the researchers observed a rapid production of immune cells from the replica bone.
This surge required the bone marrow environment to remodel, which had a profound effect on the sleeping cancer cells. More cancer cells began replicating, thereby elevating the risk of tumor formation. Gene analysis showed that HMGB2, a molecule that stimulates cell growth, increased as immune cell production surged and actively promoted the awakening of the 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. We also analyzed bone samples from people with breast or prostate cancer — HMGB2 was present where there were actively dividing cancer cells.
Ilaria Malanchi, Crick group leader
The findings suggest that normal immune responses in the bone come at the cost of disrupting tumor dormancy, tipping the balance toward reactivation and metastatic growth. However, Malanchi emphasizes that inflammation does not automatically guarantee a relapse. Instead, the team views it as a piecemeal situation where each systemic change incrementally raises the chance that more metastatic cells will wake up.
Monitoring patients during the critical post-remission period for infections, inflammation, or injuries anywhere in the body could eventually help doctors assess whether dormant cells are more likely to reactivate. Because actively replicating cancer cells can respond to chemotherapy, understanding these bone marrow developments could pave the way for early intervention.