Fibrinogen-Like Protein 2-Associated Transcriptional and Histopathological Features of Immunological Preeclampsia.

Preeclampsia is a multifactorial hypertensive disorder of pregnancy, with variable presentation in both maternal and fetal factors, such that no treatment or marker is currently universal to all cases. Here, we demonstrate that the prothrombinase and immunomodulatory secreted factor FGL-2 (fibrinogen-like protein 2) is differentially expressed across previously characterized gene expression clusters containing clinically relevant disease subtypes. FGL2 is low in a cluster consistent with the traditional paradigm of the pathology of preeclampsia (canonical preeclampsia) and high in a cluster exhibiting evidence of immune activation (immunological preeclampsia). We show that it is part of an immunoregulatory gene module integral to the transcriptional profile and placental pathology specific to immunological preeclampsia. We determine that FGL2 associates positively with chronic inflammation lesions of the placenta while associating negatively with maternal vascular malperfusion lesions. The transcriptional profiles of maternal vascular malperfusion lesions show downregulation of FGL2 and upregulation of previously investigated preeclampsia biomarkers, such as FLT1 (Fms Related Receptor Tyrosine Kinase 1) and ENG (endoglin). Conversely, the profiles of chronic inflammation lesions show an interesting downregulation of these genes, but an upregulation of FGL2 and of FGL2-correlated immunoregulatory genes, suggesting it is upregulated downstream of major inflammatory mediators such as TNF (tumor necrosis factor)-α and IFN (interferon)-γ, hallmarks of the immunological preeclampsia subtype. This work, overall, demonstrates that FGL-2 expression levels in the term placenta reflect the unique pathophysiology that leads to immunological preeclampsia, leading to its potential as a subtype-specific biomarker.

Loss of the Ste20-like kinase induces a basal/stem-like phenotype in HER2-positive breast cancers.

HER2 is overexpressed in 20-30% of all breast cancers and is associated with an invasive disease and poor clinical outcome. The Ste20-like kinase (SLK) is activated downstream of HER2/Neu and is required for efficient epithelial-to-mesenchymal transition, cell cycle progression, and migration in the mammary epithelium. Here we show that loss of SLK in a murine model of HER2/Neu-positive breast cancers significantly accelerates tumor onset and decreases overall survival. Transcriptional profiling of SLK knockout HER2/Neu-derived tumor cells revealed a strong induction in the triple-negative breast cancer marker, Sox10, accompanied by an increase in mammary stem/progenitor activity. Similarly, we demonstrate that SLK and Sox10 expression are inversely correlated in patient samples, with the loss of SLK and acquisition of Sox10 marking the triple-negative subtype. Furthermore, pharmacological inhibition of AKT reduces SLK-null tumor growth in vivo and is rescued by ectopic Sox10 expression, suggesting that Sox10 is a critical regulator of tumor growth downstream of SLK/AKT. These findings highlight a role for SLK in negatively regulating HER2-induced mammary tumorigenesis and provide mechanistic insight into the regulation of Sox10 expression in breast cancer.

Single-cell RNA-sequencing reveals transcriptional dynamics of estrogen-induced dysplasia in the ovarian surface epithelium.

Estrogen therapy increases the risk of ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. Both in vivo and in vitro, ovarian surface epithelial (OSE) cells exposed to estradiol develop a subpopulation that loses cell polarity, contact inhibition, and forms multi-layered foci of dysplastic cells with increased susceptibility to transformation. Here, we use single-cell RNA-sequencing to characterize this dysplastic subpopulation and identify the transcriptional dynamics involved in its emergence. Estradiol-treated cells were characterized by up-regulation of genes associated with proliferation, metabolism, and survival pathways. Pseudotemporal ordering revealed that OSE cells occupy a largely linear phenotypic spectrum that, in estradiol-treated cells, diverges towards cell state consistent with the dysplastic population. This divergence is characterized by the activation of various cancer-associated pathways including an increase in Greb1 which was validated in fallopian tube epithelium and human ovarian cancers. Taken together, this work reveals possible mechanisms by which estradiol increases epithelial cell susceptibility to tumour initiation.