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As an indicator of clinical prognosis, lymph node metastasis of breast cancer has drawn great attention. Many reports have revealed the characteristics of metastatic breast cancer cells, however, the effect of breast cancer cells on the microenvironment components of lymph nodes and spatial transcriptome atlas remains unclear. In this study, by integrating single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we investigate the transcriptional profiling of six surgically excised lymph node samples and the spatial organization of one positive lymph node. We identify the existence of osteoclast-like giant cells (OGC) which have high expressions of CD68 and CD163, the biomarkers of tumor-associated macrophages (TAMs). Through a spatially resolved transcriptomic method, we find that OGCs are scattered among metastatic breast cancer cells. In the lymph node microenvironment with breast cancer cell infiltration, TAMs are enriched in protumoral pathways including NF-κB signaling pathways and NOD-like receptor signaling pathways. Further subclustering demonstrates the potential differentiation trajectory in which macrophages develop from a state of active chemokine production to a state of active lymphocyte activation. This study is the first to integrate scRNA-seq and spatial transcriptomics in the tumor microenvironment of axillary lymph nodes, offering a systematic approach to delve into breast cancer lymph node metastasis.

Background: Intra-tumoral heterogeneity (ITH) is a distinguished hallmark of cancer, and cancer stem cells (CSCs) contribute to this malignant characteristic. Therefore, it is of great significance to investigate and even target the regulatory factors driving intra-tumoral stemness. c-Myc is a vital oncogene frequently overexpressed or amplified in various cancer types, including breast cancer. Our previous study indicated its potential association with breast cancer stem cell (BCSC) biomarkers. Methods: In this research, we performed immunohistochemical (IHC) staining on sixty breast cancer surgical specimens for c-Myc, CD44, CD24, CD133 and ALDH1A1. Then, we analyzed transcriptomic atlas of 1533 patients with breast cancer from public database. Results: IHC staining indicated the positive correlation between c-Myc and BCSC phenotype. Then, we used bioinformatic analysis to interrogate transcriptomics data of 1533 breast cancer specimens and identified an intriguing link among c-Myc, cancer stemness and copper-induced cell death (also known as "cuproptosis"). We screened out cuproptosis-related characteristics that predicts poor clinical outcomes and found that the pro-tumoral cuproptosis-based features were putatively enriched in MYC-targets and showed a significantly positive correlation with cancer stemness. Conclusion: In addition to previous reports on its oncogenic roles, c-Myc showed significant correlation to stemness phenotype and copper-induced cell toxicity in breast cancer tissues. Moreover, transcriptomics data demonstrated that pro-tumoral cuproptosis biomarkers had putative positive association with cancer stemness. This research combined clinical samples with large-scale bioinformatic analysis, covered description and deduction, bridged classic oncogenic mechanisms to innovative opportunities, and inspired the development of copper-based nanomaterials in targeting highly heterogeneous tumors. [ABSTRACT FROM AUTHOR]

The formation of cyclinD-CDK4/6 complex plays vital roles in the cell cycle transition from G1 phase to S phase which is characterized by vigorous transcription and synthesis. Through cyclinD-CDK4/6-Rb axis, CDK4/6 inhibitors arrest the cell cycle in the G1 phase and block the proliferation of aggressive cells, exhibiting promising effects in containing the aggressiveness of breast cancers. To date, there are three CDK4/6 inhibitors approved by the U.S. Food and Drug Administration in treating advanced hormone receptor-positive breast cancer, including palbociclib, abemaciclib, and ribociclib. In fact, several preclinical experiments and clinical trials presented therapeutic effects of CDK4/6 inhibitor-based treatment in triple-negative breast cancer. [ABSTRACT FROM AUTHOR]