Understanding the transcriptome, and the dynamics of mutational evolution, of cancer cells in vivo is still a major challenge in both basic and translational science. Highly selective tools for doing so are urgently needed. Here we demonstrate a new protected orthogonal nucleoside strategy that takes advantage of the cellular environment of cancer cells. By appending a terminally acetylated lysine chain to RNA nucleosides that contain alkyne and azide handles, we have created a way to probe the transcriptome of a cancer cell selectively, both in vitro and in vivo. The probe relies on the high histone deacetylase (HDAC) and cathepsin L protease (CatL) activities found in malignant cancers, which will selectively deacetylate and remove the lysine chain from the orthogonal nucleosides. The alkyne and azide handles on the nucleosides can then be used for click chemistry for visualization or isolation of cancer cell RNA. These new probes will provide insight into RNA profiles during all stages of tumor development, including the formation of metasases, as well as interactions with the surrounding tissues. This technology would not only permit analysis for tumor cell RNA dynamics, but also allow for analysis of tumor mutations that occur (in real time) due to drug challenge or programmed changes to the tumor niche.

Cancer cell specific RNA labeling with orthogonal nucleoside probes

2019 Spring National Meeting

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