A genetically defined disease model reveals that urothelial cells can initiate divergent bladder cancer phenotypes

Abstract

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB–up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.

Construction of heparin-based hydrogel incorporated with Cu5.4O ultrasmall nanozymes for wound healing and inflammation inhibition

“…Immunofluorescence staining We used Ki67 antibody to determine the promotion effect of Cu 5.4 O on HUVECs [ 33 ]. HUVECs were seeded in 24-well plates (5 × 10 4 cells per well) and treated with 20 μL of Hep-PEG (3.2 wt%), Cu 5.4 O (16 ng μL −1 ), or Cu 5.4 O@Hep-PEG (3.2 wt%, Cu 16 ng μL −1 gel) for 24 h. Then, cells were permeabilized with Triton X-100 (Boster, China) and blocked with 10% goat serum (Boster, China).…”

Evolution of Urothelial Bladder Cancer in the Context of Molecular Classifications

“…However, recent evidence supports the idea that SCCB originates from urothelial cells. How urothelial cells transdifferentiate remains elusive [138,140]. Possibly, anti-cancer treatments can induce the transdifferentiation of urothelial cells into tumors with a neuroendocrine phenotype in a similar manner as it has been described for neuroendocrine transdifferentiation of prostate adenocarcinoma upon androgen-deprivation therapy [141].…”

“…Neuroendocrine tumors comprise small cell carcinoma of the bladder (SCCB) and large cell carcinoma of the bladder (LCCB). SCCB is more prevalent than LCCB but is extremely rare, making up only 0.5% of BLCa, and it is usually diagnosed at late stages [138]. To date, no guidelines for the treatment of neuroendocrine tumors have been formulated.…”

“…Treatment strategies commonly follow the therapy approaches for small cell carcinoma (SCC) of the lung, including surgery, chemotherapy and radiation [139]. However, this is clearly not sufficient to treat this most aggressive form of BLCa with a 5-year overall survival rate of only~20% [138]. Very little is known about the biology and evolution of neuroendocrine tumors.…”

Screening and identification of hub genes in bladder cancer by bioinformatics analysis and KIF11 is a potential prognostic biomarker

“…Therefore, developing precise diagnostic strategies and treatments are necessary. Though numerous previous studies have revealed several insights into the pathogenesis of BC, the underlying molecular mechanisms are largely unknown (3)(4)(5). To increase the diagnostic and therapeutic accuracy of BC, it is necessary to explore the underlying molecular mechanisms.…”