Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2-positive breast cancer.

Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes.

Function of normal oral mucosa revealed by single-cell RNA sequencing.

The functions of oral mucosa include barrier, sensation, and secretion. The barrier protection function is particularly important, which includes physical barrier and immunological barrier. Few studies have revealed the function of oral mucosa by displaying the map of normal oral mucosal cells from the perspective of single cells. Here, single-cell transcriptome sequencing was used to bring a relatively comprehensive map of the normal oral mucosal cells. In total, 26,398 cells from three cases of normal oral mucosa were analyzed by single-cell RNA-sequencing and 14 distinct cell groups were defined, 7 of which were immune cells. We performed subgroup classification and heterogeneity analysis of epithelial cells, T cells, and macrophagocytes, which found a subpopulation of epithelial cells with high expression of major histocompatibility complex class II molecules, a subpopulation CD8+ GZMK+ T cells, and two kinds of active macrophagocytes. Meanwhile, we identified ligand-receptor pairs among the major cell types to explore the interactions and how they maintain the homeostasis of normal oral mucosa. Based on these results, the epithelial barrier function, immunological barrier function, and potential maintenance function of stromal cells in the oral mucosa were described at the single-cell level, which provides basic data resources for further studies of oral mucosal diseases.