Rosiglitazone and Trametinib Exhibit Potent Anti-Tumor Activity in a Mouse Model of Muscle Invasive Bladder Cancer

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients

‘Fire Burn and Cauldron Bubble’: Iron Age and Early Roman Cauldrons of Britain and Ireland

‘A man can live to 50 but a cauldron will live to 100’ – Old Kazakh sayingThis paper presents a re-examination of Iron Age and early Roman cauldrons, a little studied but important artefact class that have not been considered as a group since the unpublished study of Loughran of 1989. Cauldrons are categorised into two broad types (projecting-bellied and globular) and four groups. New dating evidence is presented, pushing the dating of these cauldrons back to the 4th centurybc. A long held belief that cauldrons are largely absent from Britain and Ireland between 600 and 200bcis also challenged through this re-dating and the identification of cauldrons dating from 600–400bc. Detailed examination of the technology of manufacture and physical evidence of use and repair indicates that cauldrons are technically accomplished objects requiring great skill to make. Many have been extensively repaired, showing they were in use for some time. It is argued that owing to their large capacity cauldrons were not used every day but were instead used at large social gatherings, specifically at feasts. The social role of feasting is explored and it is argued that cauldrons derive much of their significance from their use at feasts, making them socially powerful objects, likely to be selected for special deposition.This is the author's accepted manuscript. The final version is published by CUP in Proceedings of the Prehistoric Society: http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=9392057&fileId=S0079497X14000073

Roles of Retinoid Signaling in Urothelial Progenitor Cells

The bladder urothelium is a stratified epithelium that interconnects with the ureters to form the urinary outflow tract. A defining feature of the urothelium is its luminal population of uroplakin-expressing Superficial cells that function to create a protective, waterproof barrier. As such, proper differentiation of urothelial cell types during development and regeneration is essential for bladder function. Previous work has demonstrated that the urothelium is derived from a transient endodermal progenitor population, termed P-cells. However, two remaining uncertainties are the timing and regulation of P-cell fate. Here we show through lineage tracing that the specification of P-cells into luminal, uroplakin-expressing cell types is temporally related to the timing of endogenous retinoic acid (RA) signaling. Selective inhibition of RA signaling in P-cells through ShhCre-driven expression of the RaraT403 dominant-negative (RaraDN) mutant receptor redirected cells towards an abnormal K14+ basal fate that underwent Notch-mediated stratification into a keratinizing squamous epithelium that largely resembled epidermis. Transcriptome analysis of mutant P-cells identified aberrant expression of transcriptional regulators that have critical roles in squamous differentiation and epidermal commitment. Interestingly, inhibition of RA signaling in P-cells also resulted in improper connections between the ureters and the bladder through reduced Caspase 9-mediated apoptosis and remodeling of the common nephric duct. These observations demonstrate that RA signaling in bladder urothelial progenitor cells is required not only for proper epithelial differentiation, but also for regulating inter-organ signals that orchestrate morphogenesis of the urinary outflow tract

Polyploid Superficial Cells that Maintain the Urothelial Barrier Are Produced via Incomplete Cytokinesis and Endoreplication

Summary: The urothelium is an epithelia barrier lined by a luminal layer of binucleated, octoploid, superficial cells. Superficial cells are critical for production and transport of uroplakins, a family of proteins that assemble into a waterproof crystalline plaque that helps protect against infection and toxic substances. Adult urothelium is nearly quiescent, but rapidly regenerates in response to injury. Yet the mechanism by which binucleated, polyploid, superficial cells are produced remains unclear. Here, we show that superficial cells are likely to be derived from a population of binucleated intermediate cells, which are produced from mononucleated intermediate cells via incomplete cytokinesis. We show that binucleated intermediate and superficial cells increase DNA content via endoreplication, passing through S phase without entering mitosis. The urothelium can be permanently damaged by repetitive or chronic injury or disease. Identification of the mechanism by which superficial cells are produced may be important for developing strategies for urothelial repair. : Binucleated superficial cells are critical for urothelial barrier function. Wang et al. show that they derive from binucleated intermediate cells that form via incomplete cytokinesis. Both superficial and intermediate cells increase ploidy via endoreplication, a feature likely to be important for repair and response to environmental changes. Keywords: endoreplication, urothelium, polyploidy, epithelial barrier, regeneratio

Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer

Abstract Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

The stability of the Wnt pathway transcription factor -catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits -catenin-mediated transcription. XAV939 stimulates -catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies