Researchers at the MRC Laboratory of Medical Sciences, Imperial College London, and UCL Genetics Institute have created a detailed map of cells within breast tumors and identified distinct neighborhoods of proliferating and dormant cells, according to a July 31 announcement. The study, published in Genome Medicine, reveals that protective immune and connective cells surround hibernating cancer cells, which may shield them from treatments. The findings suggest that future therapies may need to target not only different cancer cell states but also the local environments that help them survive to halt tumor growth and prevent recurrence.
The research team used publicly available data to create a map of breast cancer tumors. They found distinct pockets of quiescent (dormant) cells surrounded by what appear to be protective guard cells. Dr. Alexis Barr, co-lead author and head of the Cell Cycle Control group at the MRC Laboratory of Medical Sciences, said, "Quiescent cancer cells are very dangerous. These cells can hide from chemotherapy and then remain in this dormant quiescent state in the tumor, and then later reactivate to drive proliferation." Barr added, "If we want to achieve long-term control of peoples' tumors and prevent tumor relapse, we have to focus on these dormant quiescent cancer cells, and have to understand more about them."
To advance this understanding, Barr collaborated with Dr. Maria Secrier's computational biology team at UCL. Together they established a detailed map using single-cell RNA sequencing combined with spatial transcriptomics. This approach allowed them to identify which genes individual cells were using while mapping their locations within the tumor.
Dr. Maria Secrier said, "We found cells that resemble therapy-resistant cells already residing in the tumor before we give any treatment," suggesting features linked to treatment resistance can be present before therapy begins. The study found this was true for both aggressive tumors and slower-developing types—a surprising result because dormancy had previously been associated mainly with slower-growing disease.
The analysis revealed that dormant regions often appeared near CXCL10-positive macrophages (a type of immune cell) and myofibroblastic cancer-associated fibroblasts (tumor-supporting connective tissue). Secrier explained, "The cancer cells are really encapsulated within these areas of macrophages and fibroblasts that we think act as shields for these dormant cancer cells... 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." She continued, "Different parts of the tumor will likely respond to different drugs... If we understand what drug combinations we can use to target both proliferative and dormant areas, potentially that could be more successful than current therapies."
According to Barr, "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 note their predictions will now need experimental testing; however, identifying built-in treatment-resistant regions in tumors may ultimately lead toward designing more effective combination therapies.
