Breast tumours may contain hidden “hibernation zones” where cancer cells stop dividing, evade chemotherapy and wait for an opportunity to return. A new study by researchers at the MRC Laboratory of Medical Sciences, Imperial College London and the UCL Genetics Institute has mapped these cellular refuges in unprecedented detail, revealing that dormant cancer cells are not isolated or randomly distributed. Instead, they appear to occupy organised neighbourhoods surrounded by immune and connective-tissue cells that may help protect them from treatment and immune attack.
The findings, published in Genome Medicine, challenge the conventional picture of a tumour as a mass of rapidly multiplying cells. Within the same tumour, researchers identified regions dominated by proliferating cancer cells alongside distinct pockets populated by quiescent cells. These dormant cells have temporarily paused their cell cycle, a biological state that makes them far less vulnerable to many chemotherapy drugs, which are designed to damage cells as they divide. Although they may be inactive, the cells can later re-enter the cell cycle and contribute to tumour growth, recurrence or metastatic spread.
“Quiescent cancer cells are very dangerous,” said Dr Alexis Barr, co-lead author and head of the Cell Cycle Control group at the MRC Laboratory of Medical Sciences. Cancer cells can enter quiescence when they encounter stresses such as limited nutrients, oxygen shortages or inadequate blood supply. Rather than dying, they reduce their activity and wait for conditions to improve. This survival strategy resembles hibernation: the cells conserve resources during hostile conditions and may reactivate after treatment has ended, when the tumour environment becomes more favourable.
To locate and characterise these cells, Barr’s team collaborated with Dr Maria Secrier’s computational biology group at UCL. The researchers integrated single-cell RNA sequencing with spatial transcriptomics, two technologies that provide complementary views of tumour biology. Single-cell RNA sequencing measures the genes active in individual cells, allowing researchers to distinguish proliferating, dormant, immune and connective-tissue populations. Spatial transcriptomics adds the missing geography by recording where those cells are located within the tumour and which other cell types occupy the surrounding tissue.
This combined approach produced a cellular map showing that features associated with treatment resistance can exist before therapy begins. The researchers detected tumour cells resembling therapy-resistant populations in untreated breast cancers, suggesting that resistance is not always created by exposure to drugs. Some resistant characteristics may already be embedded within the tumour’s cellular organisation. The pattern appeared in both aggressive breast cancer subtypes and slower-developing forms, an important observation because dormancy has often been linked primarily with less aggressive disease.
The most striking discovery was the repeated association between dormant cancer cells and two types of neighbouring cells: CXCL10-positive macrophages and myofibroblastic cancer-associated fibroblasts. Macrophages are immune cells that can perform very different functions depending on signals from their surroundings. Cancer-associated fibroblasts are connective-tissue cells reprogrammed by tumours to support tumour architecture, blood-vessel formation and disease progression. In the mapped tumours, these populations gathered around dormant cancer cells, creating what the researchers described as a potential protective shell.
The biological meaning of this arrangement remains unresolved. The surrounding macrophages and fibroblasts may actively encourage cancer cells to enter or remain in quiescence, or dormant cancer cells may recruit and reshape nearby support cells. The relationship could also operate in both directions, with tumour cells and their environment continually influencing one another. The researchers caution that the spatial association does not yet prove that these cells form a physical barrier against chemotherapy or immune cells. Experimental studies will be needed to determine whether the proposed “shield” directly protects dormant cancer cells and which molecular signals maintain the niche.
The tumour maps also revealed increased activity of the complement pathway in dormant regions. Complement is a network of immune proteins that can recognise and mark abnormal cells, regulate inflammation and influence interactions between immune and tumour cells. Its heightened activity in quiescent niches could provide a vulnerability, although the outcome may depend on the precise complement signals present and how cancer cells manipulate them. Treatments aimed at this pathway, or at the macrophages and fibroblasts surrounding dormant cells, could eventually be combined with therapies that attack actively dividing tumour cells.
The study therefore points towards a treatment strategy that targets the tumour as an ecosystem rather than as a single, uniform population. Drugs that eliminate proliferating cancer cells may leave dormant cells untouched, while therapies directed at dormant niches could disrupt the support system that enables them to survive. Combining these approaches might suppress tumour growth in the short term while reducing the reservoir of cells capable of causing relapse years later. However, the researchers emphasise that their predictions are based on computational analysis of publicly available tumour data and must be tested in laboratory models and clinical studies before they can guide treatment.
By placing dormant cancer cells on the map, the work offers a more detailed explanation of why breast cancer can return after apparently successful therapy. The danger may not lie only in a small number of unusually resilient cancer cells, but in the specialised neighbourhoods that help them persist. Understanding how cancer cells, immune cells and fibroblasts co-evolve inside these regions could enable more precise drug combinations—treating active tumour growth while dismantling the biological shelters that allow hidden disease to survive.
Subject of Research: Spatial organisation of proliferating and dormant breast cancer cells, their interactions with immune and stromal cells, and potential treatment-resistant tumour niches.
Article Title: Spatial ecology of breast cancer reveals co-evolution of proliferative and dormant niches
Web References: https://link.springer.com/article/10.1186/s13073-026-01711-0
References: Genome Medicine; DOI: 10.1186/s13073-026-01711-0
Keywords: Breast cancer, dormant cancer cells, quiescence, tumour microenvironment, spatial transcriptomics, single-cell RNA sequencing, macrophages, cancer-associated fibroblasts, complement pathway, treatment resistance, cancer recurrence, tumour niches
