Mapping the initial effects of carcinogen-induced oncogenic transformation in the mouse bladder

Abstract

Characterizing the initial stages of oncogenic transformation allows the identification of tumor-promoting processes before the inherent clonal selection of the aggressive clones. Here, we used global proteomics, genetic cell tracing, and immunofluorescence to dynamically map the very early stages of cancer initiation in a mouse model of bladder cancer. We observed a very rapid and incremental proteome dysregulation, with changes in the energy metabolism, proliferation and immune signatures dominating the landscape. The changes in the lipid metabolism were immediate and defined by an increase fatty acid metabolism and lipid transport, followed by the activation of the immune landscape. Alongside the changes in the immune signature and lipid metabolism, we also mapped a clear increase in the cell cycle-related pathways and proliferation. Proliferation was mainly restricted to the basal epithelial layer rapidly leading to urothelium thickening, despite the progressive loss of the superficial layer. Moreover, we observed a tilt in the energy balance towards increased glucose metabolism, probably characterizing cells of the tumor microenvironment. All of the observed proteome signature changes were persistent, being retained and sometimes intensified or diversified along the timeline. The signatures observed in this pilot suggest these processes as potentially targetable drivers of the future neoplastic transformations in the bladder.