Researchers from the MRC Laboratory of Medical Sciences (LMS), Imperial College London and the UCL Institute of Genetics have constructed a detailed cellular map of breast tumours, revealing separate regions filled with actively dividing cancer cells and others containing dormant cells. Published in Genome medicineThe findings show that these dormant cancer cells are often surrounded by immune and connective tissue cells that can help protect them from treatment.
The work suggests that future cancer therapies may need to do more than target fast-growing tumor cells. They may also need to target dormant cancer cells and the local environments that allow them to persist, with the goal of stopping tumor growth while reducing the risk of the disease returning later.
Cells hidden inside breast tumors
Breast tumors are complex environments made up of many different types of cells. Alongside the rapidly multiplying cancer cells are immune cells, newly formed blood vessels, and a particularly worrying group of cancer cells that remain unusually silent.
These dormant or “quiescent” cells can survive treatment and may later help the cancer spread or come back. Researchers at LMS, Imperial and UCL wanted to understand where these cells are found in untreated tumours, what sets them apart and what other cells tend to surround them.
Using publicly available data, the team created detailed maps of breast cancer tumors and found distinct groups of dormant cells surrounded by other cells that can serve as a protective barrier.
Why dormant cancer cells are dangerous
“Inactive cancer cells are very dangerous,” explains Dr. Alexis Barr, co-senior author and head of the LMS Cell Cycle Control group. “These cells can hide from chemotherapy and then remain in this dormant state in the tumor, and then reactivate to drive proliferation.”
Cancer cells can enter this dormant state in response to stressful conditions within a growing tumor. As tumors expand rapidly, blood flow and nutrients may not always keep pace. Some cells respond by basically slowing down their growth.
Like a bear hibernating in harsh conditions, these cells can remain dormant until the environment becomes more favorable. That opportunity may arise after treatment is completed.
Alexis adds: “If we want to achieve long-term control of people’s tumors and prevent tumor relapse, we need to focus on these dormant cancer cells and understand more about them.”
Cell-by-cell tumor mapping
To investigate these hidden cell populations, Alexis worked with Dr Maria Secrier’s computational biology team at UCL to build a detailed picture of the tumor and the immune and supporting cells surrounding it.
The researchers combined single-cell RNA sequencing, which reveals which genes individual cells are using, with spatial transcriptomics, a technique that shows where those cells are located and which neighboring cells are nearby.
“We found cells that look like therapy-resistant cells that already reside in the tumor before we administer any treatment,” Maria says, suggesting that some features associated with treatment resistance may already exist before therapy begins rather than appearing only as a response to treatment.
The researchers observed this pattern in both aggressive forms of breast cancer and slower-growing classes, an unexpected result because inactivity has previously been more closely linked to slower-growing disease.
Protective neighborhoods around inactive cells
The analysis extended beyond the cancer cells themselves. The researchers also examined the numerous types of supporting cells that become part of the tumor environment.
A consistent pattern emerged. The dormant cancer cells were frequently located near CXCL10-positive macrophages (a type of immune cell) and cancer-associated myofibroblastic fibroblasts (a type of tumor supporting cell).
These surrounding cells may have been recruited or altered in ways that help protect dormant cancer cells. One possibility is that they create a physical or biological barrier that prevents immune cells or cancer-killing treatments from effectively reaching dormant cells.
“The cancer cells are actually encapsulated within these areas of macrophages and fibroblasts that we think act as shields for these dormant cancer cells,” Maria said. “But we still don’t know the direction of cause and effect: whether the surrounding cells push the cancer cells into a state of dormancy or whether the cancer cells attract or alter their environment. It is very likely that it comes from both sides.”
Different tumor regions may require different treatments
Many chemotherapy drugs work best against cells that divide rapidly. However, dormant cells do not actively multiply, which can make them much more difficult to remove.
The findings suggest that dormant and rapidly growing parts of the same tumor may respond differently to treatment. The researchers detected increased activity in the complement pathway (a part of the immune system) within niches of inactive cells. That raises the possibility that treatments targeting this pathway could make those areas more vulnerable.
Support cells surrounding dormant cancer cells could provide another potential treatment target. However, researchers still need to determine whether these cells actually help maintain dormancy and how important they are to cancer cell survival.
“Different parts of the tumor are likely to respond to different drugs,” Maria said. “If we understand what combinations of drugs we can use to target both proliferative and inactive areas, they could potentially be more successful than current therapies. This gives us a first idea of how we can intervene with different therapies that specifically target different areas of the tumor where the cells have adapted and evolved differently.”
Alexis said: “It’s clearly important to focus on proliferative cancer cells, but we also need to understand this population of dormant, quiescent cancer cells. And that’s been less studied.”
A possible path towards longer lasting treatments
The ideas generated by this analysis remain to be tested experimentally. Still, locating treatment-resistant regions that already exist within tumors and understanding the cells that support them could eventually help researchers develop more effective combinations of cancer therapies.
By mapping dormant cells and the environments around them, scientists can design treatments that attack both the rapidly growing parts of a tumor and dormant cells that can survive and then become active again.
This work was primarily funded by a Future Leaders Fellowship from UKRI, the Medical Research Council and the Biotechnology and Biological Sciences Research Council.