Cancer Res. 2022 Aug 15. pii: CAN-21-3819. [Epub ahead of print]
Yicheng Wang,
Haoling Xie,
Xiaohong Chang,
Wenqi Hu,
Mengyao Li,
Yi Li,
Huiping Liu,
Hongyan Cheng,
Shang Wang,
Ling Zhou,
Danhua Shen,
Sha Dou,
Ruiqiong Ma,
Yunuo Mao,
Honglan Zhu,
Xiaobo Zhang,
Yuxuan Zheng,
Xue Ye,
Lu Wen,
Kehkooi Kee,
Heng Cui,
Fuchou Tang.
High-grade serous cancer (HGSC) is the most common subtype of ovarian cancer. HGSC is highly aggressive with poor patient outcomes, and a deeper understanding of HGSC tumorigenesis could help guide future treatment development. To systematically characterize the underlying pathological mechanisms and intratumoral heterogeneity in human HGSC, we used an optimized single-cell multiomics sequencing technology to simultaneously analyze somatic copy number alterations (SCNA), DNA methylation, chromatin accessibility, and transcription in individual cancer cells. Genes associated with interferon (IFN) signaling, metallothioneins, and metabolism were commonly upregulated in ovarian cancer cells. Integrated multiomics analyses revealed that upregulation of IFN signaling and metallothioneins was influenced by both demethylation of their promoters and hypomethylation of satellites and LINE1, and potential key transcription factors regulating glycolysis using chromatin accessibility data were uncovered. Additionally, gene expression and DNA methylation displayed similar patterns in matched primary and metastatic tumor cells of the same genetic lineage, suggesting that metastatic cells potentially preexist in subclones of primary tumors. Finally, the lineages of cancer cells with higher residual DNA methylation levels and upregulated expression of CCN1 and HSP90AA1 presented greater metastatic potential. This study characterizes the critical genetic, epigenetic, and transcriptomic features and their mutual regulatory relationships in ovarian cancer, providing valuable resources for identifying new molecular mechanisms and potential therapeutic targets for HGSC.