Breast cancer cells can survive in bone marrow for years after primary treatment.
Out of all challenges in oncology, metastasis is still the toughest obstacle, responsible for the highest proportion of mortality linked to the disease. Cancer cells that have moved to another part of the body can stay dormant for years after the original tumour has been treated,
notes Crick group leader Ilaria Malanchi, who leads a lab studying how cancer cells interact with the rest of the body.
Patients face an anxious waiting period during remission, uncertain whether these hidden cells will reactivate. Breast cancer cells routinely target the bone marrow, settling into tissue that normally supports blood cell production. These disseminated cells slip into a quiescent sleeping state, evading both immune surveillance and chemotherapy drugs that rely on active cell division.
Engineering an Extramedullary Bone Model to Track Sleeping Metastatic Cells
Studying dormancy has long frustrated researchers because mice do not live long enough to watch dormant cells spontaneously awaken over five-year spans. To solve this limitation, Stefania di Blasio and Tatiana Rizou in Malanchi’s team built upon prior work by Laurie Gay to engineer an innovative extramedullary bone model. Grown from skeletal stem cells beneath the skin, this artificial bone contains the necessary marrow components to manufacture new blood cells and react to inflammatory signals.
We then added cells from a mouse mammary tumour onto the replica bone.
Ilaria Malanchi, Crick group leader
Most of the introduced tumour cells settled into a dormant state with only sporadic replication activity. This breakthrough model finally allowed researchers to test what specific insults could shake resting cancer cells out of their hibernation.
Gut Inflammation and HMGB2 Surge Drive Tumour Awakening
While localized bone fractures are known to encourage metastatic growth, researchers investigated whether indirect injuries or infections elsewhere in the body could spark similar danger. By inducing intestinal colitis in mice hosting the artificial bone, gut inflammation triggered a rapid production of immune cells from the replica bone.
Remodeling the bone marrow environment to boost immune cell output profoundly impacted the sleeping cancer cells. Active replication surged, heightening the risk of tumour formation. Genetic analysis revealed that the growth-stimulating molecule HMGB2 increased alongside the surge in immune cell production. Simply increasing HMGB2 inside the artificial bone without any outside inflammation was enough to activate sleeping cancer cells, and human bone samples from breast and prostate cancer patients showed HMGB2 present wherever active cell division occurred.
Mapping Protective Niches and Cell Interactions in Breast Tumours
Parallel insights into tumour complexity emerge from complementary research published in Genome Medicine by scientists at the MRC Laboratory of Medical Sciences, Imperial College London, and UCL Genetics Institute. Using single-cell RNA sequencing and spatial transcriptomics, researchers mapped both individual cell types and their exact locations within untreated breast tumours.
The team discovered that quiescent cancer cells frequently sit adjacent to CXCL10-positive macrophages and myofibroblastic cancer-associated fibroblasts. These surrounding cells form a protective shield that helps hidden cancer cells elude immune attacks or therapy. Researchers detected heightened complement pathway activity within these dormant niches, pointing to additional avenues for future exploration.
Monitoring Infections During Remission for Early Intervention
Systemic changes do not trigger a relapse automatically. Malanchi points out that the process happens gradually, with every bodily shift raising the probability that additional dormant cancer cells will rouse on each occasion. Tracking patients for infections, injuries, or systemic inflammation during their vulnerable post-remission window could reveal when dormant populations are most vulnerable to reactivation.
Because actively replicating cancer cells regain vulnerability to chemotherapy, understanding bone marrow dynamics opens the door to timely therapeutic intervention before full relapse occurs.
