Proper placental development requires extravillous trophoblast (EVT) differentiation and invasion into the maternal decidua to remodel spiral arteries and support fetal growth. Disruptions in these processes contribute to preeclampsia and fetal growth restriction. These pregnancy complications are common in women with immune-mediated inflammatory diseases, which are characterized by elevated levels of pro-inflammatory cytokines such as interferon-α (IFN-α) and tumor necrosis factor-α (TNF-α). However, the direct effects of these cytokines on EVTs remain unclear. Using human trophoblast organoid models, we demonstrate that IFN-α and TNF-α impair EVT invasion while preserving differentiation capacity. High-resolution imaging of untreated organoid-decidua co-cultures revealed extensive trophoblast invasion into decidual stroma and arteries, but invasion was substantially reduced particularly upon IFN-α treatment. Transcriptome profiling identified changes in several invasion-related pathways after cytokine exposure. These findings suggest that elevated IFN-α and TNF-α can directly impair trophoblast invasive capacity, potentially contributing to suboptimal placental development in inflammatory disorders.

SummaryThe mechanisms underlying sex differences in glioblastoma (GBM) incidence, treatment response, and survival are not well understood. Increased activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling is associated with shorter survival in GBM. We looked at the expression of NF-κB- or STAT3-related genes in GBM for evidence of a sex skew in activity. Survival analysis of male and female GBM patients revealed that NF-κB- or STAT3-related gene expression was correlated with shorter survival only in female patients. We further explored mechanisms of this sex effect in an established murine model of sex differences in GBM. Concordant with human data, female murine GBM cells expressed stronger signatures of NF-κB and STAT3 genes and exhibited stronger responses to pathway stimulation and inhibition than their male counterparts. This study illustrates the advantage of sex-stratified data analysis in the development of sex-informed treatments for greater precision in cancer treatments. Graphical abstract Highlights•Female GBM patients with upregulated NF-κB/STAT3 signaling have shorter survival•In murine GBM, NF-κB and STAT3 signaling exhibit sex differences•Female murine GBM cells are more sensitive to NF-κB and STAT3 inhibition•Sex-informed use of drugs targeting these pathways could benefit female patients Health disparity; Cancer

The prostate is a gland that contributes to men's fertility. It is highly responsive to androgens and is often the site of carcinogenesis, as prostate cancer is the most frequent cancer in men in over a hundred countries. To study the normal prostate, few in vitro models exist, and most of them do not express the androgen receptor (AR). To overcome this issue, prostate epithelial cells can be grown in primary culture ex vivo in 2- and 3-dimensional culture (organoids). However, methods to purify these cells often require flow cytometry, thus necessitating specialized instruments and expertise. Herein, we present a detailed protocol for the harvest, purification, and primary culture of mouse prostate epithelial cells to grow prostate organoids ex vivo. This protocol does not require flow cytometry approaches, facilitating its implementation in most research laboratories, and organoids grown with this protocol are highly responsive to androgens. In summary, we present a new simple method that can be used to grow prostate organoids that recapitulate the androgen response of this gland in vivo.