RESUMO
Serous endometrial carcinoma (SEC) constitutes about 10% of endometrial carcinomas and is one of the most aggressive and lethal types of uterine cancer. Due to the rapid progression of SEC, early detection of this disease is of utmost importance. However, molecular and cellular dynamics during the pre-dysplastic stage of this disease remain largely unknown. Here, we provide a comprehensive census of cell types and their states for normal, pre-dysplastic, and dysplastic endometrium in a mouse model of SEC. This model is associated with inactivation of tumor suppressor genes Trp53 and Rb1 , whose pathways are altered frequently in SEC. We report that pre-dysplastic changes are characterized by an expanded and increasingly diverse immature luminal epithelial cell populations. Consistent with transcriptome changes, cells expressing the luminal epithelial marker TROP2 begin to substitute FOXA2+ cells in the glandular epithelium. These changes are associated with a reduction in number and strength of predicted interactions between epithelial and stromal endometrial cells. By using a multi-level approach combining single-cell and spatial transcriptomics paired with screening for clinically relevant genes in human endometrial carcinoma, we identified a panel of 44 genes suitable for further testing of their validity as early diagnostic and prognostic markers. Among these genes are known markers of human SEC, such as C DKN2A, and novel markers, such as OAS2 and OASL, members of 2-5A synthetase family that is essential for the innate immune response. In summary, our results suggest an important role of the luminal epithelium in SEC pathogenesis, highlight aberrant cell-cell interactions in pre-dysplastic stages, and provide a new platform for comparative identification and characterization of novel, clinically relevant prognostic and diagnostic markers and potential therapeutic modalities.
RESUMO
Microbial conversion of plant biomass to value-added products is an attractive option to address the impacts of petroleum dependency. In this study, a bacterial system was developed that can hydrolyze xylan and utilize xylan-derived xylose for growth and production of polyhydroxyalkanoates (PHAs). A ß-xylosidase and an endoxylanase were engineered into a P(LA-co-3HB)-producing Escherichia coli strain to obtain a xylanolytic strain. Although PHA production yields using xylan as sole carbon source were minimal, when the xylan-based media was supplemented with a single sugar (xylose or arabinose) to permit the accumulation of xylan-derived xylose in the media, PHA production yields increased up to 18-fold when compared to xylan-based production, and increased by 37 % when compared to production from single sugar sources alone. ¹H-Nuclear magnetic resonance (NMR) analysis shows higher accumulation of xylan-derived xylose in the media when xylan was supplemented with arabinose to prevent xylose uptake by catabolite repression. ¹H-NMR, gel permeation chromatography, and differential scanning calorimetry analyses corroborate that the polymers maintain physical properties regardless of the carbon source. This study demonstrates that accumulation of biomass-derived sugars in the media prior to their uptake by microbes is an important aspect to enhance PHA production when using plant biomass as feedstock.
