Distinct Transcriptional Programs in Ascitic and Solid Cancer Cells Induce Different Responses to Chemotherapy in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is responsible for the largest number of ovarian cancer deaths. The frequent therapy-resistant relapses necessitate a better understanding of mechanisms driving therapy resistance. Therefore, we mapped more than a hundred thousand cells of HGSOC patients in different phases of the disease, using single-cell RNA sequencing. Within patients, we compared chemonaive with chemotreated samples. As such, we were able to create a single-cell atlas of different HGSOC lesions and their treatment. This revealed a high intrapatient concordance between spatially distinct metastases. In addition, we found remarkable baseline differences in transcriptomics of ascitic and solid cancer cells, resulting in a different response to chemotherapy. Moreover, we discovered different robust subtypes of cancer-associated fibroblasts (CAF) in all patients. Besides inflammatory CAFs, vascular CAFs, and matrix CAFs, we identified a new CAF subtype that was characterized by high expression of STAR, TSPAN8, and ALDH1A1 and clearly enriched after chemotherapy. Together, tumor heterogeneity in both cancer and stromal cells contributes to therapy resistance in HGSOC and could form the basis of novel therapeutic strategies that differentiate between ascitic and solid disease. IMPLICATIONS: The newly characterized differences between ascitic and solid cancer cells before and after chemotherapy could inform novel treatment strategies for metastatic HGSOC.

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance.

Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effectively implemented in clinical trials, more research is needed to elucidate the mechanisms leading to EMT-induced therapy resistance.

ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition.

BACKGROUND: Epithelial mesenchymal transition (EMT) is tightly regulated by a network of transcription factors (EMT-TFs). Among them is the nuclear factor ZEB2, a member of the zinc-finger E-box binding homeobox family. ZEB2 nuclear localization has been identified in several cancer types, and its overexpression is correlated with the malignant progression. ZEB2 transcriptionally represses epithelial genes, such as E-cadherin (CDH1), by directly binding to the promoter of the genes it regulates and activating mesenchymal genes by a mechanism in which there is no full agreement. Recent studies showed that EMT-TFs interact with epigenetic regulatory enzymes that alter the epigenome, thereby providing another level of control. The role of epigenetic regulation on ZEB2 function is not well understood. In this study, we aimed to characterize the epigenetic effect of ZEB2 repressive function on the regulation of a small Rab GTPase RAB25. RESULTS: Using cellular models with conditional ZEB2 expression, we show a clear transcriptional repression of RAB25 and CDH1. RAB25 contributes to the partial suppression of ZEB2-mediated cell migration. Furthermore, a highly significant reverse correlation between RAB25 and ZEB2 expression in several human cancer types could be identified. Mechanistically, ZEB2 binds specifically to E-box sequences on the RAB25 promoter. ZEB2 binding is associated with the local increase in DNA methylation requiring DNA methyltransferases as well as histone deacetylation (H3K9Ac) depending on the activity of SIRT1. Surprisingly, SIRT1 and DNMTs did not interact directly with ZEB2, and while SIRT1 inhibition decreased the stability of long-term repression, it did not prevent down-regulation of RAB25 and CDH1 by ZEB2. CONCLUSIONS: ZEB2 expression is resulting in drastic changes at the chromatin level with both clear DNA hypermethylation and histone modifications. Here, we revealed that SIRT1-mediated H3K9 deacetylation helps to maintain gene repression but is not required for the direct ZEB2 repressive function. Targeting epigenetic enzymes to prevent EMT is an appealing approach to limit cancer dissemination, but inhibiting SIRT1 activity alone might have limited effect and will require drug combination to efficiently prevent EMT.

Unusual presentation of trocar site hernia after Roux-en-Y gastric bypass: case report.

INTRODUCTION: The exponential increase of bariatric surgery has resulted in a new diagnostic field of postoperative complications. One of the possibly serious complications is trocar site hernia. CASE REPORT: We present a rare case of trocar site hernia, in particular herniation of the blind loop of the jejunojejunostomy in a patient previously operated for laparoscopic gastric bypass. CONCLUSION: In patients with intermittent epigastric pain and regurgitation or nausea after RYGB, the differential diagnosis should include internal herniation and cholecystitis. Besides that, incarcerated trocar site hernia should also be considered. If obstructive symptoms are lacking, this might indicate Richter's hernia or herniation of the blind loop of the jejunojejunostomy. Due to the vague symptoms and the potentially late presentation, diagnosis can be challenging. However, this is a dangerous complication possibly leading to bowel strangulation and perforation, requiring urgent surgical repair.

Sacral neuromodulation with an implantable pulse generator in children with lower urinary tract symptoms: 15-year experience.

PURPOSE: Sacral nerve modulation with an implantable pulse generator is not an established treatment in children. This therapy has been described for dysfunctional elimination syndrome and neurogenic bladder. We report 2 new indications for this approach in children, ie bladder overactivity and Fowler syndrome. The aim of this study was to improve the results of future treatment for sacral neuromodulation in children by describing factors favorable for good outcomes with this method. MATERIALS AND METHODS: A total of 18 children 9 to 17 years old were studied. Mean ± SD followup was 28.8 ± 43.8 months. Of the patients 16 underwent S3 sacral neuromodulation and 7 underwent pudendal stimulation (5 as a revision, 2 from the beginning). RESULTS: Initial full response was achieved in 9 of 18 patients (50%) and partial response in 5 (28%). In patients presenting with incontinence mean ± SD number of incontinence episodes weekly improved significantly from 23.2 ± 12.4 to 1.3 ± 2.63 (p <0.05). In patients requiring clean intermittent catheterization there was a significant decrease in mean ± SD daily frequency of catheterization from 5.2 ± 1.6 to 2.0 ± 1.9 (p <0.05). At the end of the study 6 of 15 patients (40%) had a full response and 5 (33%) had a partial response, while 4 implantable pulse generator devices (27%) were explanted because of failure. CONCLUSIONS: Sacral neuromodulation is feasible in the pediatric population, with good short-term (78% full or partial response) and satisfactory long-term results (73%). Sacral neuromodulation can offer good results for overactive bladder, dysfunctional elimination syndrome and Fowler syndrome. Pudendal nerve stimulation is a feasible salvage treatment that can be useful in cases when S3 implantation is impossible or unsuccessful.