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Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer.

PURPOSE
The heterogeneity of high-grade serous ovarian cancer (HGSOC) is not well studied, which severely hinders clinical treatment of HGSOC. Thus, it is necessary to characterize the heterogeneity of HGSOC within its tumor microenvironment (TME).


EXPERIMENTAL DESIGN
The tumors of seven treatment-naïve HGSOC patients at early or late stages and five age-matched non-malignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq).


RESULTS
A total of 59,324 single cells obtained from HGSOC and non-malignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of EMT-associated gene signature, in which NOTCH1, SNAI2, TGFBR1 and WNT11 was further selected as a genetic panel to predict the poor outcomes of HGSOC patients. Matrix CAFs (mCAFs) expressing α-SMA, vimentin, COL3A, COL10A and MMP11, were the dominant CAFs in HGSOC tumors and could induce epithelial-to-mesenchymal transition (EMT) properties of OC cells in the co-culture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM and TEX cells were preferentially enriched in early-stage tumors. Additionally, an immune co-inhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce OC tumor growth in mouse models.


CONCLUSIONS
Our transcriptomic results analyzed by scRNA-seq delineate a ecosystemic landscape of HGSOC at early or late stages with a focus on its heterogeneity with TME. The major applications of our findings are a four EMT-gene model for prediction of HGSOC patient outcomes, mCAFs' capability of enhancing OC cell invasion and potential therapeutic value of anti-TIGIT treatment.