Malignant epithelial diversification and inflammatory neutrophil remodeling define a transitional stage between tumor cell dissemination and overt metastatic outgrowth in breast cancer

Breast cancer metastasis remains the leading cause of mortality, yet the biology behind the transition from disseminated cancer cells to overt metastasis is still not well understood. This is partly because it is difficult to capture experimentally the phase between dissemination and metastatic outgrowth.

In a study using a genetically engineered mouse model, researchers explored this transition by examining pre-nodular lungs, tissues where disseminated tumor cells are present but no metastatic nodules have formed yet. The study found a unique subset of malignant epithelial cells, marked by the combination of CD104, CD24, and CD61, which were more common in these pre-nodular lungs.

This group of malignant epithelial cells showed distinct transcriptional programs, such as epithelial plasticity, stress adaptation, motility, and immune evasion. At the same time, pre-nodular lungs experienced an increase in mature Cxcr2 neutrophils. These neutrophils had an inflammatory and tissue-remodeling program, distinguished from less harmful neutrophil states.

Both these changes in malignant epithelial cells and inflammatory neutrophils were also observed in human aggressive breast cancer metastases and were linked to shorter distant metastasis-free survival and poor clinical outcomes. This research provides a framework for investigating biomarkers and therapeutic targets during this crucial phase of metastatic progression, where many disseminated cancer cells either die or successfully advance towards forming metastases.