Characterization of chemotherapy resistant triple-negative breastcancers at single-cell resolution

Triple-negative breast cancer is a highly aggressive and heterogeneous disease with an average survival of lessthan ۵۰% and a median progression free survival of ۱.۷ months for women who have therapy resistant metastaticdisease . Although immunotherapy is showing promising results in early triple-negative breast cancer , manypatients do not respond, and chemotherapy remains the main treatment option . High rates of recurrence intriple-negative breast cancer are in part due to its inherent molecular heterogeneity and sub-clonal diversity,in which cells present in minority sub-populations escape the pressures of therapy . Here we sought to char acterise the transcriptomic sub-clonal diversity of chemotherapy resistant triple-negative breast tumors. Sixteenprimary untreated triple-negative breast tumours (۸ chemosensitive, and ۸ chemoresistant, who died of their dis ease within three years of initial diagnosis) were sequenced using the single nuclei RNA-seq to characterise theinter- and intra- sample transcriptomic heterogeneity. Unsupervised meta-clustering of epithelial cells in G۱ phaseof cell cycle from all samples identified three clusters that were shared between chemoresistant and chemosen sitive patients, six clusters that were dominated by cells from chemoresistant, and ten clusters dominated bycells from chemo-sensitive patients. Top significant markers of each cluster were tested for enrichment in GObiological process and pathway databases using the Fisher’s exact test (hypergeometric distribution). The meta clusters based on enriched biological process illustrated a clear distinction between chemoresistant-dominant andchemosensitive-dominant meta-clusters. For instance, chemoresistant-dominant meta-clusters exhibited enrichmentfor biological functions related to the interaction of tumour cells with immune cells. Further, some meta-clusterswere enriched for known markers of disease aggression such as the EMT, ERBB۲ and tumour hypoxia pathways

کلیدواژه ها:

Triple-negative breast cancer ، chemoresistant ، single-cell ، sub-clonal heterogeneity