Introduction:
Recently, it has been revealed that bladder cancer (BC) and upper tract urothelial carcinoma (UTUC) are biologically distinct diseases. Mouse models of bladder carcinogenesis have been established using N-butyl-N-(4-hydro-oxybutyl) nitorosamine (BBN) for a long time, but there are few reports of upper tract urothelial carcinogenesis with high incidence. Therefore, the UTUC carcinogenesis mouse model is expected in the area of basic research on UTUC. The aim of this study is to establish a novel mouse model of UTUC carcinogenesis and evaluate its genetic similarity to human UTUC to assess its applicability for future basic research on UTUC, and to elucidate its carcinogenic mechanism.
Methods:
We used two strains (C57/BL6 and BALB/c) of male and female mice and fed 0.05% BBN from 6 weeks old to the harvest day. Both sides of upper urinary tract from mice drinking BBN or tap water were subjected to whole exome sequencing (WES) and whole transcriptome sequencing (WTS) to assess its genetic similarity to human UTUC. A representative UTUC sample was subjected to spatial transcriptomic sequencing to assess its heterogeneity. Characteristic metabolic differences in feces between UTUC mice and healthy mice were evaluated by semi-targeted metabolomics method.
Results:
Only BALB/c female showed higher incidence of UTUC than BC, while the other strains rarely had UTUC. The total incidence of UTUC in BALB/c female was 83.3%, with the earliest UTUC observed at 8 weeks after BBN treatment. Mutational pattern of this model and frequent mutated gene list showed similarity to human UTUC. This model had no FGFR3 mutation, a result consistent with previously reported BBN-BC model, suggesting that it mimics UTUC with poor prognosis. In terms of gene expression, this model belonged basal subtype, with spatially heterogeneous in each sample. Metabolomic analysis revealed that alanine was the most important factor in feces to distinct UTUC mice to healthy mice. Alanine restriction in diet suppressed UTUC carcinogenesis but not BC carcinogenesis.
Conclusion:
Firstly, we have established a novel mouse model developing UTUC that genetically mimics human UTUC. Secondly, alanine restriction can suppress UTUC carcinogenesis in this model.
Funding: N/A
Image(s) (click to enlarge):
Alanine restriction can inhibit carcinogenesis in a novel mouse model of upper tract urothelial carcinoma
Category
Bladder Cancer > Upper Tract Urothelial Carcinoma
Description
Poster #46
Thursday, November 30
8:00 a.m. - 9:00 a.m.
Presented By: Akinaru Yamamoto
Authors:
Akinaru Yamamoto
Atsunari Kawashima
Nesrine Sassi
Yuki Horibe
Akihiro Yoshimura
Masaru Tani
Yohei Okuda
Toshiki Oka
Toshihiro Uemura
Gaku Yamamichi
Yu Ishizuya
Yoshiyuki Yamamoto
Taigo Kato
Koji Hatano
Norio Nonomura