Abstract
Molecular mechanisms underlying breast cancer lymph node metastasis remain unclear. Using single-cell sequencing, we investigated the transcriptome profile of 96,796 single cells from 15 paired samples of primary tumors and axillary lymph nodes. We identified nine cancer cell subclusters including CD44 + / ALDH2 + /ALDH6A1 + breast cancer stem cells (BCSCs), which had a copy-number variants profile similar to that of normal breast tissue. Importantly, BCSCs existed only in primary tumors and evolved into metastatic clusters infiltrating into lymph nodes. Furthermore, transcriptome data suggested that NECTIN2-TIGIT-mediated interactions between metastatic breast cancer cells and tumor microenvironment (TME) cells, which promoted immune escape and lymph node metastasis. This study is the first to delineate the transcriptome profile of breast cancer lymph node metastasis using single-cell RNA sequencing. Our findings offer novel insights into the mechanisms underlying breast cancer metastasis and have implications in developing novel therapies to inhibit the initiation of breast cancer metastasis.
Highlights
Breast cancer is the most common malignancy among women and a frequent cause of cancer-related deaths resulting from metastasis [1]
Across multiple studies conducted over the years, no single best delineation has been identified to understand the transcriptome diversity of metastatic breast cancer at a single-cell level, nor were comparisons made between primary tumors and lymph node metastases
differentiated expressed genes (DEGs), and functional enrichment showed the potential sensitivity for immunotherapy in that immune-related items were highly enriched in metastatic triple-negative breast cancer (TNBC) cells (Fig. 3A). β2-microglobulin, which is encoded by B2M, is an essential component of Single-cell transcriptome analysis of primary breast cancer
Summary
Breast cancer is the most common malignancy among women and a frequent cause of cancer-related deaths resulting from metastasis [1]. Across multiple studies conducted over the years, no single best delineation has been identified to understand the transcriptome diversity of metastatic breast cancer at a single-cell level, nor were comparisons made between primary tumors and lymph node metastases. We investigated the cellular composition and transcriptome profiles of five primary tumors and ten paired axillary lymph nodes, demonstrating the heterogeneity of breast cancer, and identified the top differentiated expressed genes (DEGs) associated with breast cancer lymph node metastasis. TIGIT are found to hamper immunity against breast cancer; by between tumor sites and evolutionary state, metastatic cancer expressing TIMP-1, BCSC promotes epithelial-mesenchymal transi- cells were at later stages, while the primary lesion held more cells tion (EMT) by interacting with CD63 in epithelial cells [15,16,17,18,19]. DEGs, and functional enrichment showed the potential sensitivity for immunotherapy in that immune-related items were highly enriched in metastatic TNBC cells (Fig. 3A). β2-micro-
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