Here, Kayko investigated the proteomic landscape changes along a timeline within the 12 days of treatment with a potent carcinogen, BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine), to understand how oncogenic transformation occurs in mouse bladder. By combining transgenic models, TMT-plex proteomics, pathway analysis, cell biology and single-cell transcriptomics, we described the initial effects and molecular changes characterising the gradual transition from healthy to injured bladder. Further on we compared these proteomic signatures with single cell transcriptomics of bladder mucosa after long-term BBN treatment (22-weeks) inducing invasive tumours to identify the cellular component involved in this transformation. Moreover, we compared out data sets with a previously identified predictive signature in a global proteome study on patients diagnosed with non-muscle invasive bladder cancer (NMIBC), where we identified molecular cancer signatures in several of the apparently healthy biopsies. This comparison revealed a large number of pathways having a similar activity pattern in between the mouse and human counterparts, including immune, cell cycle, growth and antioxidant signalling. By using the observed molecular landscape identified by The Cancer Genome Atlas (TCGA) network, we identified in our proteomic dataset the significant regulation of several TCGA markers (Ank3, Ccnd3, Crebbp, Erbb2, Frem2, Hras, Rxra, Zfp36l1) at day-12 post-BBN, despite being considerable earlier time point than described in these studies.
We showed that:
- BBN exposure induces very rapid changes in the urothelium.
- Lipid metabolism, immune and proliferation signature change in the first 4 days of exposure.
- Proliferation is significantly increased in the basal urothelial layer leading to thickening.
- The energy metabolism is tilted towards increased glucose metabolism under two weeks into BBN treatment.
- All observed proteome signature changes were persistent.
- Established markers of bladder neoplasia were detected as early as D12 of exposure.
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Mapping the initial effects of carcinogen-induced oncogenic transformation in the mouse bladder.
Authors: Hossain MK, Unger L, Larsen U, Altankhuyag A, Legøy TA, Paulo JA, Vethe H, Ghila L.
Experimental Cell Research 2025 Feb 21:114452
DOI information: 10.1016/j.yexcr.2025.114452