Walch-Rueckheim, B. | Search bioRxiv

bioRxiv2023

Th17 cells target the metabolic miR-142-5p-SDHC/SDHD axis promoting invasiveness and progression of cervical cancers

During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients. We previously demonstrated that Th17 cells are associated with therapy resistance as well as cervical cancer metastases and relapse, however, the underlying Th17-driven mechanisms supporting cervical cancer progression are not fully understood as yet. In this study, we found that Th17 cells promote migration and invasion of cervical cancer cells in 2D cultures and 3D spheroids. We demonstrated that Th17 cells induced the expression of miR-142-5p in cervical cancer cells supporting their migration and invasiveness. As the responsible mechanism, we identified the subunits C and D of the succinate dehydrogenase (SDH) complex as new targets of miR-142-5p and provided evidence that Th17 cells reduced the expression of SDHC and SDHD that was dependent on miR-142-5p. Functional downstream analysis with inhibitors of miR-142-5p and siRNA knock down of SDHC and SDHD revealed that Th17-induced miR-142-5p-mediated reduced expression of SDHC and SDHD was responsible for enhanced migration and invasion of cervical cancer cells. Consistently, cervical cancer patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patients' biopsies significantly correlated with increased numbers of Th17 cells, advanced tumor stage and lymph node metastases. Correspondingly, a combination of weak or negative SDHD expression and a ratio of Th17/CD4+ T cells > 43.90 % in situ was associated with reduced recurrence free survival. In summary, we unraveled a novel molecular mechanism by which Th17 cells promote cervical cancer progression and suggest evaluation of Th17 cells as a potential target for immunotherapy in cervical cancer.

cancer biology↗

bioRxiv2019

Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program

Herpesvirus infection initiates a range of perturbations in the host cell, which remain poorly understood at the level of individual cells. Here, we quantified the transcrips of single human primary fibroblasts during the first hours of lytic infection with HSV-1. By applying a generalizable analysis scheme, we defined a precise temporal order of early viral gene expression and found unexpected bifurcations and bottlenecks. We identified individual host cell genes and pathways relevant in early infection by combining three different computational approaches: gene and pathway overdispersion analysis, prediction of cell-state transition probabilities as well as future cell states. One transcriptional program, which was turned on in infected cells and correlated with increased resistance to infection, implicated the transcription factor NRF2. Consequently, Bardoxolone methyl, a known NRF2 agonist, impaired virus production, suggesting that NRF2 activation restricts the progression of viral infection. Our study provides novel insights into early stages of HSV-1 infection and serves as a general blueprint for the investigation of heterogenous cell states in virus infection.

systems biology↗