A new study has mapped the cellular and metabolic features of lymph node metastasis in breast cancer, revealing key mechanisms that allow cancer to spread. The research, published in The American Journal of Pathology by Elsevier, uses advanced single-cell RNA sequencing and spatial transcriptomics to analyze how tumor cells interact with their environment.
Breast cancer is the second most common cancer worldwide and represents about 23.8% of all cases among women. Lymph node metastasis is a major factor leading to poor outcomes for patients, but its underlying molecular drivers have not been well understood.
Researchers examined more than 360,000 cells from 78 matched primary breast cancer and lymph node metastasis samples. They identified ten main cell types, including epithelial, immune, and stromal cells. A distinct group of early disseminated cancer cells (EDCs) was found within the epithelial population. These EDCs showed increased invasive potential through changes in metabolism—such as higher glycolysis and hypoxia response—and by altering immune responses to help tumors survive and evade detection.
The team also found a complex communication network between lymphocytes, macrophages, and epithelial cells in metastatic tissue. M2-type macrophages were shown to secrete cytokines like CCL22 and CXCL12, which create an immunosuppressive environment while encouraging the transformation of EDCs into more aggressive forms. Spatial transcriptomics confirmed that these interactions occur in specific regions near where tumors invade lymph nodes.
"This systemic interaction between cancer cells, metabolism, and immunity is the core mechanism of lymph node metastasis and a potential therapeutic target," said Tingming Liang, PhD, co-lead investigator from Nanjing Normal University.
The researchers identified four tyrosine kinase inhibitors—including pexidartinib hydrochloride and sunitinib malate—that can block M2 macrophage function by targeting CSF1R. This action suppresses the immunosuppressive activity that supports metastasis.
"These drugs have demonstrated safety in treating other cancers, and our findings provide a theoretical basis for their application in breast cancer metastasis," noted Dr. Guo. "Future work will need to explore the metabolic vulnerabilities of EDCs and integrate clinical data to advance the development of innovative therapeutic strategies for patients."
