Scientists Find Dormant Breast Cancer Cells Hiding Behind Protective Cell 'Shields'

Researchers from the MRC Laboratory of Medical Sciences (LMS), Imperial College London, and the UCL Genetics Institute have built a detailed cellular map of breast tumors, revealing separate regions filled with actively dividing cancer cells and others containing dormant, or "quiescent," cells. The findings, published in the journal Genome Medicine, show that these inactive cancer cells are often surrounded by immune and connective tissue cells that may help protect them from treatment.

Dormant cancer cells can survive chemotherapy by essentially hibernating inside a tumor, later reactivating to drive its growth. "Quiescent cancer cells are very dangerous," said Dr. Alexis Barr, co-lead author and head of the Cell Cycle Control group at the LMS. "These cells can hide from chemotherapy and then remain in this dormant quiescent state in the tumor, and then later reactivate to drive proliferation." Cancer cells can enter this dormant state under the stressful conditions of a rapidly growing tumor, when blood flow and nutrients may not keep pace, and can remain inactive until the environment becomes more favorable, an opportunity that may arise after treatment ends.

Working with Dr. Maria Secrier's computational biology team at UCL, Barr combined single-cell RNA sequencing, which reveals which genes individual cells are using, with spatial transcriptomics, which shows where those cells are positioned and which neighbors are nearby. "We found cells that resemble therapy-resistant cells already residing in the tumor before we give any treatment," Secrier said, suggesting some resistance-related traits may exist before therapy begins rather than appearing only in response to it. The researchers saw the same pattern in both aggressive and slower-developing breast cancers, an unexpected result since quiescence had previously been linked more closely with slower-growing disease.

Dormant cancer cells were frequently found close to CXCL10-positive macrophages, a type of immune cell, and myofibroblastic cancer-associated fibroblasts, a type of tumor-supporting cell. "The cancer cells are really encapsulated within these areas of macrophages and fibroblasts that we think act as shields for these dormant cancer cells," Secrier said. "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."

The researchers also detected increased activity in the complement pathway, part of the immune system, within these dormant cell niches, raising the possibility that treatments targeting that pathway could make the areas more vulnerable. "Different parts of the tumor will likely respond to different drugs," Secrier said. "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."