Investigator
First Affiliated Hospital Zhejiang University
Benzo[a]pyrene reduces cellular senescence in ovarian cancer by stabilizing c-Myc independently of DNA damage
Benzo[a]pyrene (BaP), a widespread environmental pollutant produced by the incomplete combustion of organic materials and cigarette smoke, has been linked to the promotion of cancer progression. In this study, we demonstrated that BaP not only enhances cisplatin resistance but also suppresses cellular senescence. Importantly, these effects occur independently of DNA damage. Mechanistically, BaP binds to the Thr58 site of c-Myc, preventing its phosphorylation at this residue. This interaction reduces c-Myc ubiquitination, resulting in its stabilization and increased oncogenic activity. The accumulation of c-Myc subsequently drives the expression of genes associated with tumor growth, metastasis, and drug resistance. Our findings uncover a novel mechanism through which environmental pollutants like BaP influence cancer biology, offering a theoretical basis for the prevention and management of such exposures. This research highlights the critical role of environmental factors in cancer development and identifies potential therapeutic targets to counteract the effects of these harmful compounds.
Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer
Abstract 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 7 treatment-naïve patients with HGSOC at early or late stages and five age-matched nonmalignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq). Results: A total of 59,324 single cells obtained from HGSOC and nonmalignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of epithelial-to-mesenchymal transition (EMT)-associated gene signatures, in which a combination of NOTCH1, SNAI2, TGFBR1, and WNT11 was further selected as a genetic panel to predict the poor outcomes of patients with HGSOC. Matrix cancer-associated fibroblasts (mCAF) expressing α-SMA, vimentin, COL3A, COL10A, and MMP11 were the dominant CAFs in HGSOC tumors and could induce EMT properties of ovarian cancer cells in the coculture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM, and TEX cells were preferentially enriched in early-stage tumors. In addition, an immune coinhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce ovarian cancer tumor growth in mouse models. Conclusions: Our transcriptomic results analyzed by scRNA-seq delineate an 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 ovarian cancer cell invasion and potential therapeutic value of anti-TIGIT treatment.
