Disease relapse is a major concern in breast cancer patients. A small number of cancer cells survive the initial treatment regimen, resulting in re-occurrence of the disease in almost 20 to 40% of patients, often within a few years. Such resistant cancer cells are referred to as Minimum residual disease (MRD). Isolating these cells from patients is very challenging. Additionally, characterizing and specifically targeting these group of cells remains a major hurdle in the treatment landscape of breast cancers.
Ksenija et al. have addressed these issues in their recent study which was published in the journal Molecular systems biology. The researchers have used an inducible pre-clinical mouse model which can be switched on and off accordingly. Using this model, they have isolated normal, tumour and residual cells, and cultured them as organoids (3D culture). Next, metabolic and methylation (epigenetic) changes among these cells were analysed using multiomics approaches. The methylation and metabolic patterns were found to be similar between residual and tumours cells, yet were different from normal cells. However, the residual cells do differ from earlier tumour cells on two accounts. They neither show the highly proliferative propensity nor the oncogenic signalling seen in the tumour cells.
Researchers demonstrate that these MRD cells carry a unique memory in form of elevated glycolysis which is used to generate energy (ATP) for cellular metabolism. These findings were also validated in patients who had received chemotherapy. Importantly, these cells can be targeted with a small molecule (inhibitor of glycolysis) that inhibits metabolic pathway in MRD without affecting normal cells.
In conclusion, the researchers have developed a unique way in which targeted treatment options for residual cells can be developed. Also, the technique of culturing these residual cells as organoids can be used to isolate and maintain residual cells from breast cancer patients for longer duration. These cells can be used to test the efficacy of new/existing drugs, and provide treatment options tailored for specific patients.
Radic Shechter K, Kafkia E, Zirngibl K, Gawrzak S, Alladin A, Machado D, et al. Metabolic memory underlying minimal residual disease in breast cancer. Mol Syst Biol. 2021 Oct;17(10):e10141.