64 Researchers have created a detailed map of cells within breast tumours, revealing distinct neighbourhoods of rapidly dividing and dormant cancer cells. The study suggests that immune and connective tissue cells may help shield dormant cancer cells, allowing them to survive treatment and potentially contribute to the disease returning. Breast tumours contain a complex mix of cell types. Alongside rapidly dividing cancer cells are immune cells, newly formed blood vessels, and a population of dormant, or quiescent, cancer cells. Although these cells are inactive, they can evade treatment and may later contribute to cancer recurrence or spread. Researchers at the MRC Laboratory of Medical Sciences, Imperial College London, and UCL Genetics Institute set out to investigate where these quiescent cells are located within untreated breast tumours, what distinguishes them, and which surrounding cells they interact with. Using publicly available datasets, the team created a detailed map of breast tumours and identified distinct pockets of quiescent cells surrounded by immune and connective tissue cells that may provide a protective environment. “Quiescent cancer cells are very dangerous,” explained Dr Alexis Barr, co-lead author of the study and head of the Cell Cycle Control Group at the MRC. “These cells can hide from chemotherapy and then remain in this dormant quiescent state in the tumour, and then later reactivate to drive proliferation.” Some cancer cells enter this dormant state in response to the stressful conditions inside a tumour, where nutrients and blood supply may struggle to keep pace with rapid growth. Like a bear hibernating through harsh conditions, they remain inactive until the environment becomes more favourable, potentially after treatment has finished. Dr Barr added: “If we want to achieve long term control of peoples’ tumours and prevent tumour relapse, we have to focus on these dormant quiescent cancer cells, and have to understand more about them.” To investigate further, Dr Barr collaborated with Dr Maria Secrier’s computational biology team at the UCL to create a detailed map of tumour cells and the surrounding immune and support cells. The researchers combined single-cell RNA sequencing, which identifies the genes individual cells are expressing, with spatial transcriptomics, which maps the location of cells and their neighbours within the tumour. “We found cells that resemble therapy-resistant cells already residing in the tumour before we give any treatment,” said Dr Secrier. This suggests that features associated with treatment resistance may already be present within tumours, rather than developing only in response to therapy. The researchers observed this pattern in both aggressive and slower-growing tumour types, a surprising finding because quiescence had previously been linked mainly to slower-growing disease. The team’s analysis mapped not only cancer cells but also the diverse support cells within the tumour microenvironment. They identified a recurring pattern: dormant cancer cells were frequently located close to CXCL10-positive macrophages, a type of immune cell, and myofibroblastic cancer-associated fibroblasts, a type of tumour-supporting cell. The researchers suggest these surrounding cells may help protect dormant cancer cells by creating a local environment that shields them from cancer-fighting immune cells or the effects of treatment. “The cancer cells are really encapsulated within these areas of macrophages and fibroblasts that we think act as shields for these dormant cancer cells,” said Dr Secrier. “But we don’t yet know the direction of cause and effect: whether the surrounding cells push cancer cells into dormancy or if the cancer cells attract or alter their surroundings. It’s very likely coming from both sides.” Many chemotherapy drugs are most effective against rapidly dividing cells. However, dormant cancer cells may respond differently to treatment. The study suggests that proliferating and dormant regions within the same tumour could have distinct drug sensitivities. The analysis also found increased activity in the complement pathway, part of the immune system, within dormant tumour niches. This may make these regions susceptible to therapies targeting the pathway. The surrounding support cells could also represent a potential therapeutic target, although their role in maintaining cancer cell dormancy has yet to be confirmed. “Different parts of the tumour will likely respond to different drugs,” said Dr Secrier. “If we understand what drug combinations we can use to target both the proliferative and the dormant areas, potentially that could be more successful than current therapies. This is giving us a first insight into how we can then intervene with different therapeutics that specifically target different areas of the tumour where the cells have adapted and have evolved differently.” Dr Barr added: “It is clearly important to focus on proliferative cancer cells, but we also need to understand this population of quiescent dormant cancer cells. And that’s been less studied.” The researchers say the predictions generated by the study will now need to be tested experimentally. Identifying treatment-resistant regions that are already present within tumours, and understanding the support systems that help sustain them, could ultimately help researchers develop more effective combination therapies. Mapping the location and characteristics of quiescent cancer cells may also provide new opportunities to improve long-term cancer treatment. The research was primarily funded by a UKRI Future Leaders Fellowship, the Medical Research Council, and the Biotechnology and Biological Sciences Research Council. The study was published in Genome Medicine.