Project description:The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH can be accurately measured when informed by the molecular signatures of the normal cells of origin. We surveyed the transcriptomes of ~ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ~1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.
Project description:Epithelial ovarian cancer (EOC) is the most lethal malignancy of the female reproductive system. In order to improve EOC patient outcomes, it is crucial to have a better understanding of how EOC develops from its cellular origin. EOCs can originate from either fallopian tube epithelial (FTE) cells or ovarian surface epithelial (OSE) cells, but with different courses of development. The basis for this difference is unclear. To address this, we performed single cell RNA-sequencing of mouse cells isolated from the distal portion of fallopian tubes (i.e., oviducts) and surface layer of ovaries. Analysis of this single cell dataset revealed distinct niche organizations for murine FTE cells and OSE cells.
Project description:Chlamydia trachomatis is the causative agent of sexually transmitted disease with the highest prevalence in the world today. Although, sensitive to antibiotic treatment, Ctr is also a major cause of infertility due to significant cell damage caused to the genital tract of affected women. Occlusion of Fallopian tubes is a frequent consequence of advanced ascending Ctr infection. So far the mechanisms of Ctr caused pathogensis are widely unclear. Here we show, by using an ex vivo infection model of human Fallopian tubes that Ctr causes changes in epithelial homeostasis within 2 days of inoculation, by disrupting cell adhesion and increasing cell proliferation. We demonstrate by imaging and expression analysis that tissue response to invading pathogen has also a paracrine component. We identify Wnt signalling activation as one of the hallmarks of Ctr infection which transmits effects of the infection beyond inclusion containing cells. Mechanisms of phenotypic changes involve up regulation of Epcam and Olfactomedin 4, biomarkers and regulators of cell adhesion and cell differentiation. Our findings bring focus to the pleiotropic effects of Ctr infection within epithelium and could be provide the basis for better understanding the pathological sequels in vivo.
Project description:Chlamydia trachomatis is the causative agent of sexually transmitted disease with the highest prevalence in the world today. Although, sensitive to antibiotic treatment, Ctr is also a major cause of infertility due to significant cell damage caused to the genital tract of affected women. Occlusion of Fallopian tubes is a frequent consequence of advanced ascending Ctr infection. So far the mechanisms of Ctr caused pathogensis are widely unclear. Here we show, by using an ex vivo infection model of human Fallopian tubes that Ctr causes changes in epithelial homeostasis within 2 days of inoculation, by disrupting cell adhesion and increasing cell proliferation. We demonstrate by imaging and expression analysis that tissue response to invading pathogen has also a paracrine component. We identify Wnt signalling activation as one of the hallmarks of Ctr infection which transmits effects of the infection beyond inclusion containing cells. Mechanisms of phenotypic changes involve up regulation of Epcam and Olfactomedin 4, biomarkers and regulators of cell adhesion and cell differentiation. Our findings bring focus to the pleiotropic effects of Ctr infection within epithelium and could be provide the basis for better understanding the pathological sequels in vivo. Microarray experiments were performed as dual-color hybridizations. To compensate for dye-specific effects, an independent dye-reversal color-swap was applied. Quality control and quantification of total RNA amount was assessed using an Agilent 2100 bioanalyzer (Agilent Technologies) and a NanoDrop 1000 spectrophotometer (Kisker).
Project description:The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH can be accurately measured when informed by the molecular signatures of the normal cells of origin. We surveyed the transcriptomes of ~ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ~1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.
Project description:Hydrosalpinx is common cause of tubal factor infertility in women in which the fallopian tube becomes blocked, fills with fluid, and consequently is nonfunctional. Single cell RNA-seq analysis has provided an unparalleled approach to characterize tissue types and explore pathologies in unbiased manner. Here we use scRNA-seq to define and compare major and rare cell types of the human fallopian tube in the healthy and hydrosalpinx disease state.
Project description:Fallopian tube epithelium is the tissue-of-origin of most high grade serous papillary ovarian carcinoma. This tumor has been exensively investigated and sequenced but expression profiling data of normal fallopian tube epithelial cells is still rare. This project compares the miRNA profiles of high grade serous papillary ovarian tumors (FFPE and fresh frozen) to that of normal unmatched epithelial cells from resected fallopian tubes.
Project description:The fallopian tube transports the gametes to the fertilization site and delivers the embryo to the uterus at the optimal time for implantation. Progesterone and the classical progesterone receptor (PGR) are known to be involved in regulating both tubal ciliary beating and muscular contractions, possibly involving both genomic and non-genomic actions. To provide more clues on the mechanisms involved, we investigated the effect of progesterone on gene expression in mice fallopian tubes in vitro at early (20 min) and later (2 h, 8 h) time-points using microarray and/or quantitative PCR. In parallel, oocyte cumulus complex transport was investigated in ovulating mice injected with one of the PGR antagonists, Org 31710 or CDB2194. Microarray analyses did not reveal any apparently regulated genes 20 min after progesterone treatment, in agreement with a proposed non-genomic action of progesterone controlling ciliary beating. After 2 h, 11 genes were significantly up-regulated. Analyses by quantitative PCR at 2 h and 8 h showed a consistent up-regulation of endothelin 1 (Edn1) and a down-regulation of its receptor Ednra by progesterone. We also show that treatment with progesterone receptor antagonist before ovulation accelerates the transport of the oocyte cumulus complex. This is the first study showing that progesterone regulates Edn1 and Ednra in the fallopian tube. Together with previous studies on endothelin-mediated effects on muscular contractions in the fallopian tube, the results from this study suggest that endothelin is a mediator of the progesterone-controlled effects on muscular contraction, and eventually gamete transport, in the fallopian tube. 16 pooled samples from mice fallopian tubes were exposed in vitro to progesterone for up to 2 hours.