Spatiotemporal microenvironment landscape and malignant epithelial pattern transition in breast ductal carcinoma progression.

Background: Owing to the complexity of TME components and the heterogeneity of cancer cells, the relationship between the niches of TME and prognosis in breast ductal carcinoma remains unknown. The staged characteristics of corresponding cancer cell behaviors are unclear. Our study aims to reveal spatial structures and specific cellular information of TME and cancer cells subgroups during the progression from DCIS to IDC and lymph node metastasis.

Methods: Single-cell sequencing, spatial transcriptomics, bulk RNA sequencing datasets were used to explore the changes in microenvironmental components and transcriptional programs of tumor cells during the progression of breast ductal carcinoma. Immunohistochemistry, multiplex immunofluorescence, flow cytometry cell cycle detection, invasion migration experiments, and WB imprinting were employed for validation.

Results: Analysis of TME cell type subsets revealed the accumulation of T_EX, iTreg, and stress-phenotype TAM in the mammary gland in situ during the invasion process. Lymphatic metastases exhibited enrichment of nTregs and a more naïve-like CD8 T cell population. Spatial analysis and survival analysis showed that the spatial niches of CD4 T_N and phagocytic-phenotype macrophages were associated with a favorable prognosis, and these niches were lost during disease progression. The proliferative subpopulation of breast ductal carcinoma was enriched in lymphatic metastatic tissues, expressing high levels of FAM111B and exhibiting intense TCA and oxidative phosphorylation metabolism. Silencing FAM111B led to cell cycle arrest, decreased invasion and migration abilities, and downregulation of core mediator genes for cuproptosis and disulfidptosis.

Conclusions: The stage-specific microenvironmental characteristics of breast ductal carcinoma correspond to some extent to the behavior of tumor cells. During the progression of ductal carcinoma in breast tissue, the establishment of an immunosuppressive microenvironment occurs. The microenvironmental spectrum at lymph node metastases differs somewhat, corresponding to a more enriched turnover of cancer cell proliferation and death. Inhibitors of FAM111B and inducers of cuproptosis and disulfidptosis may serve as potential therapeutic targets for proliferative subgroups.