Canonical and non-Canonical Target-directed microRNA degradation controls cell fitness and transcriptional plasticity in breast cancer

A recently discovered mechanism, termed target-directed miRNA degradation (TDMD), involves certain RNA transcripts ("triggers") inducing the degradation of miRNAs ("substrates"). The extent of TDMD regulation in human cancer and its implications in cancer phenotypes remain poorly understood.

Here, we fill this gap identifying miRNA substrates that accumulate post-transcriptionally upon TDMD blockade in a panel of breast cancer cell lines. Our approach identified 31 high-confidence miRNA substrates, with a few miRNAs - including miR-7, miR-29b and miR-33a/b - controlled by degradation in multiple cell types. Combining transcriptome-wide mapping of miRNA:mRNA interactions by eCLIP with single cell RNA sequencing analysis of intratumor heterogeneity, we found that NREP limits the expression and activity of miR-29b in triple-negative breast cancer (TNBC) cell lines, fine tuning the transcriptional and phenotypic plasticity of cells along the epithelial-to-mesenchymal trajectory.