Grainyhead-Like 3 Influences Migration and Invasion of Urothelial Carcinoma Cells.

Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential expression of GRHL3 was assessed in normal human urothelium and in non-invasive and invasive bladder cancer cell lines. The contribution of GRHL3 to cell proliferation, viability and invasion in UCB cell lines was determined by gain- and loss-of-function assays in vitro and in an organ culture model using de-epithelialized porcine bladders. GRHL3 expression was detectable in normal human urothelial cells and showed significantly higher mRNA and protein levels in well-differentiated, non-invasive RT4 urothelial carcinoma cells compared to moderately differentiated RT112 cells. GRHL3 expression was absent in anaplastic and invasive T24 cells. Ectopic de novo expression of GRHL3 in T24 cells significantly impaired their migration and invasion properties in vitro and in organ culture. Its downregulation improved the invasive capacity of RT4 cells. The results indicate that GRHL3 may play a role in progression and metastasis in UCB. In addition, this work demonstrates that de-epithelialized porcine bladder organ culture can be a useful, standardized tool to assess the invasive capacity of cancer cells.

[Organoids as a milestone on the way to personalized treatment of urothelial carcinoma: a systematic review]. / Organoide als Meilenstein auf dem Weg zur personalisierten Therapie des Urothelkarzinoms: ein systematischer Review.

BACKGROUND: The treatment options for locally advanced and metastatic urothelial carcinoma (UC) are currently limited to established chemotherapy and immunotherapy protocols. Targeted treatment is so far restricted to a small subgroup of patients. Urothelial organoid systems could make a decisive contribution in establishing effective personalized treatment options by enabling drug response prediction through testing the sensitivity of individual patients. The aim of this article is to describe the state of the science of clinically applicable organoid systems for UC. METHODOLOGY: A systematic literature search was conducted in several medical databases (Medline, Cochrane Library) and study registers (ClinicalTrials.gov, the EU Clinical Trials Register and the WHO International Clinical Trials Registry). The search terms and the search strategy were adapted to the databases used. RESULTS: Overall, 7 studies met the inclusion criteria on the topic of UC organoids. These studies describe the fundamental workflow in establishing organoid systems in patients with tumors of the urinary bladder or the renal pelvis. The success rates in generating organoids from non-muscle-invasive bladder cancer were 70-77% and for muscle-invasive bladder cancer 42%. For patient organoids systematic drug testing was carried out. CONCLUSION: The generation of UC organoids is feasible and the ex vivo testing of individual treatment forms is possible. Due to the lack of a standardized methodology, their implementation remains experimental at the moment. The methodology has a high potential to provide a personalized treatment concept to patients with urothelial cancer.

[Impact of the COVID-19 pandemic on urology residency training programs in Germany]. / Auswirkungen der COVID-19 Pandemie auf die urologische Weiterbildung in Deutschland.

BACKGROUND: Several international medical societies reported a negative impact on urology residency training programs due to the COVID-19 pandemic. OBJECTIVES: The aim of this study was to investigate the impact of the pandemic on urological residency in Germany. MATERIALS AND METHODS: From the 20th of May 2020 until the 20th of June 2020, a Germany-wide online survey on the continuing residency training was distributed via the members of the working group, social media (Facebook, Twitter, Instagram) and the German Society of Residents in Urology (GeSRU e.V.) newsletter. The survey covered 3 topics: 1) basic characteristics of the participants, 2) general and 3) subjective influence of the COVID-19 pandemic on clinics and further residency training. RESULTS: A total of 50 residents took part in the survey; 54% were women. The median age was 31 years. Most of the participants were in their 2nd (22%) and 5th (26%) year of training and worked in a university hospital (44%) or in a clinic of maximum care (30%). 38% of the respondents stated that they only served urological emergencies during the COVID-19 pandemic. For 28% this meant a very large delay (80-100%) in the specialisation, while 28% stated only a minor impact. 66% documented training impairments caused by fewer operations, low patient numbers in the outpatient department (50%), congress (50%) and workshop (44%) cancellations. 46% of residents reported direct contact with COVID-19 patients while 10% were deployed on interdisciplinary IMC units. Numerous physical distancing and hygiene measures have been implemented by the clinics. CONCLUSION: On average, around 50% of the urology residents indicated significant restrictions in training due to the COVID-19 pandemic in Germany. The delay in training cannot currently be measured in units of time, but it can be assumed that training for residents during the pandemic is likely to be of a lower quality compared to previous generations.

Organoids at the PUB: The Porcine Urinary Bladder Serves as a Pancreatic Niche for Advanced Cancer Modeling.

Despite intensive research and progress in personalized medicine, pancreatic ductal adenocarcinoma remains one of the deadliest cancer entities. Pancreatic duct-like organoids (PDLOs) derived from human pluripotent stem cells (PSCs) or pancreatic cancer patient-derived organoids (PDOs) provide unique tools to study early and late stage dysplasia and to foster personalized medicine. However, such advanced systems are neither rapidly nor easily accessible and require an in vivo niche to study tumor formation and interaction with the stroma. Here, the establishment of the porcine urinary bladder (PUB) is revealed as an advanced organ culture model for shaping an ex vivo pancreatic niche. This model allows pancreatic progenitor cells to enter the ductal and endocrine lineages, while PDLOs further mature into duct-like tissue. Accordingly, the PUB offers an ex vivo platform for earliest pancreatic dysplasia and cancer if PDLOs feature KRASG12D mutations. Finally, it is demonstrated that PDOs-on-PUB i) resemble primary pancreatic cancer, ii) preserve cancer subtypes, iii) enable the study of niche epithelial crosstalk by spiking in pancreatic stellate and immune cells into the grafts, and finally iv) allow drug testing. In summary, the PUB advances the existing pancreatic cancer models by adding feasibility, complexity, and customization at low cost and high flexibility.