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Abstract Within ovarian cancer research, patient-derived xenograft (PDX) models recapitulate histologic features and genomic aberrations found in original tumors. However, conflicting data from published studies have demonstrated significant transcriptional differences between PDXs and original tumors, challenging the fidelity of these models. We employed a quantitative mass spectrometry-based proteomic approach coupled with generation of patient-specific databases using RNA-seq data to investigate the proteogenomic landscape of serially-passaged PDX models established from two patients with distinct subtypes of ovarian cancer. We demonstrate that the utilization of patient-specific databases guided by transcriptional profiles increases the depth of human protein identification in PDX models. Our data show that human proteomes of serially passaged PDXs differ significantly from their patient-derived tumor of origin. Analysis of differentially abundant proteins revealed enrichment of distinct biological pathways with major downregulated processes including extracellular matrix organization and the immune system. Finally, we investigated the relative abundances of ovarian cancer-related proteins identified from the Cancer Gene Census across serially passaged PDXs, and found their protein levels to be unstable across PDX models. Our findings highlight features of distinct and dynamic proteomes of serially-passaged PDX models of ovarian cancer.

Abstract Trophoblast stem cells (TSCs) give rise to specialized cell types within the placenta. However, the regulatory mechanisms that guide trophoblast cell fate decisions during placenta development remain ill defined. Here we exploited ATAC-seq and transcriptional profiling strategies to describe dynamic changes in gene expression and chromatin accessibility during TSC differentiation. We detect significantly increased chromatin accessibility at key genes upregulated as TSCs exit from the stem cell state. However, downregulated gene expression is not simply due to the loss of chromatin accessibility in proximal regions. Additionally, transcriptional targets recognized by the zinc finger transcriptional repressor Prdm1/Blimp1, an essential regulator of placenta development, were identified in ChIP-seq experiments. Comparisons with previously reported ChIP-seq datasets for primordial germ cell-like cells and E18.5 small intestine, combined with functional annotation analysis revealed that Blimp1 has broadly shared as well as cell type-specific functional activities unique to the trophoblast lineage. Importantly, Blimp1 not only silences TSC gene expression but also prevents aberrant activation of divergent developmental programmes. Overall the present study provides new insights into the chromatin landscape and Blimp1-dependent regulatory networks governing trophoblast gene expression.

The zinc finger transcriptional repressor Prdm1/Blimp1 is essential for remodelling maternal blood vessels in a subset of trophoblast cells. Here, the authors perform single-cell RNA-seq analysis on this Blimp1+ lineage, identifying functionally distinct cell types present at the maternal–foetal interface.

Nature Communications 7: Article number: 11414 (2016), Published 25 April 2016; Updated 23 November 2018 In the original version of this Article, the accession codes section within the Methods was inadvertently omitted. This section has now been added in both the PDF and HTML versions of the Article.