Pirfenidone alleviates fibrosis by acting on tumour-stroma interplay in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a 5-year survival rate of 12%. The abundant mesenchyme is partly responsible for the malignancy. The antifibrotic therapies have gained attention in recent research. However, the role of pirfenidone, an FDA-approved drug for idiopathic pulmonary fibrosis, remains unclear in PDAC. METHODS: Data from RNA-seq of patient-derived xenograft (PDX) models treated with pirfenidone were integrated using bioinformatics tools to identify the target of cell types and genes. Using confocal microscopy, qRT-PCR and western blotting, we validated the signalling pathway in tumour cells to regulate the cytokine secretion. Further cocultured system demonstrated the interplay to regulate stroma fibrosis. Finally, mouse models demonstrated the potential of pirfenidone in PDAC. RESULTS: Pirfenidone can remodulate multiple biological pathways, and exerts an antifibrotic effect through inhibiting the secretion of PDGF-bb from tumour cells by downregulating the TGM2/NF-kB/PDGFB pathway. Thus, leading to a subsequent reduction in collagen X and fibronectin secreted by CAFs. Moreover, the mice orthotopic pancreatic tumour models demonstrated the antifibrotic effect and potential to sensitise gemcitabine. CONCLUSIONS: Pirfenidone may alter the pancreatic milieu and alleviate fibrosis through the regulation of tumour-stroma interactions via the TGM2/NF-kB/PDGFB signalling pathway, suggesting potential therapeutic benefits in PDAC management.

PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells.

Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.

Construction of a novel risk model based on the random forest algorithm to distinguish pancreatic cancers with different prognoses and immune microenvironment features.

Immune-related long noncoding RNAs (irlncRNAs) are actively involved in regulating the immune status. This study aimed to establish a risk model of irlncRNAs and further investigate the roles of irlncRNAs in predicting prognosis and the immune landscape in pancreatic cancer. The transcriptome profiles and clinical information of 176 pancreatic cancer patients were retrieved from The Cancer Genome Atlas (TCGA). Immune-related genes (irgenes) downloaded from ImmPort were used to screen 1903 immune-related lncRNAs (irlncRNAs) using Pearson's correlation analysis (R > 0.5; p < 0.001). Random survival forest (RSF) and survival tree analysis showed that 9 irlncRNAs were highly correlated with overall survival (OS) according to the variable importance (VIMP) and minimal depth. Next, Cox regression analysis was used to establish a risk model with 3 irlncRNAs (LINC00462, LINC01887, RP11-706C16.8) that was evaluated by Kaplan-Meier analysis, the areas under the curve (AUCs) of the receiver operating characteristics and the C-index. Additionally, we performed Cox regression analysis to establish the clinical prognostic model, which showed that the risk score was an independent prognostic factor (p < 0.001). A nomogram and calibration plots were drawn to visualize the clinical features. The Wilcoxon signed-rank test and Pearson's correlation analysis further explored the irlncRNA signatures and immune cell infiltration, as well as the immunotherapy response.

Applications of single-cell sequencing in cancer research: progress and perspectives.

Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.

Effects of endometrial preparations and transferred embryo types on pregnancy outcome from patients with advanced maternal age.

We explored the strategy of frozen-thawed embryo transfer (FET) in the women with advanced maternal age (AMA). We first determined the age cut-off point of AMA by retrospective analysis of pregnancy outcomes in the patients undergoing FET. The patients with AMA were divided into 3 groups including natural cycle (NC) group, controlled ovarian stimulation (COS) group, and hormone replacement therapy (HRT) group, and simultaneously were divided into 2 groups including cleavage-stage embryo transfer (CET) group and blastocyst-stage embryo transfer (BET) group. The clinical pregnancy, embryo implantation, abortion and live birth rates were compared between the 3 groups and the 2 groups, respectively. We found that in the women aged 38 years or over, the clinical pregnancy rate and live birth rate were all significantly decreased as compared with the younger than 38-year-old women (all P < 0.05), so the women aged 38 years or over were regarded as the patients with AMA in this study. In the patients with AMA, the clinical pregnancy rate and live birth rate were 22.95% and 18.03% in NC group, 23.68% and 15.79% % in COS group as well as 24.58% and 15.92% in HRT group, and there were no significant differences in the clinical pregnancy rate and live birth rate between the 3 groups. However, the clinical pregnancy rate (42.96% vs 15.87%) and embryo implantation rate (32.26% vs 9.67%) were all significantly higher in the BET group than in the CET group (all P < 0.01). We conclude that in the women aged 38 years or over, the choice of endometrial preparation protocols may depend on the individual specific conditions because the endometrial preparation protocols do not affect FET outcome, but BET can obtain better FET outcomes as compared with CET. Abbreviations: AMA: advanced maternal age; FET: frozen-thawed embryo transfer; NC: natural cycle; COS: controlled ovarian stimulation; HRT: hormone replacement therapy; CET: cleavage-stage embryo transfer; BET: blastocyst-stage embryo transfer; LH: luteinizing hormone; HCG: human chorionic gonadotropin; HMG: human menopausal gonadotropin; FSH: follicle-stimulating hormone; BMI: body mass index.