Non-encoded Mechanisms of Stress Adaptation in Cancer

Abstract

Tumour resistance attributed to clonal evolution of neoplastic cells, poses a major challenge for treatment of cancer. Clonality of neoplastic cells is mainly considered to reflect heterogeneity of the mutational landscape. Emerging evidence suggests alternative “non-encoded” routes to tumour resistance, e.g. by clonal competition. Notably, upstream mediators of “non-encoded” tumour resistance remain largely unknown. Herein, we explore two non-encoded mechanisms that reprogram the heterogeneity of SKBR3 breast cancer cells in vitro. MicroRNA-4673, encoded in notch1 locus, synchronises cycling neoplastic cells into G0 by targeting cyclin-dependent kinase-18 (cdk18), a key component of G0-G1 checkpoint. Enhanced autophagic flux subsequent to upregulation of miRNA-4673 renders SKBR3 cells more resistant to genotoxic stressors. We next investigated the global molecular platform that is exploited by miRNA-4673 to improve the fitness of neoplastic cells. Several small molecule inhibitors were utilised to program the subcellular distribution of catenin-β1, a major driver of cell cycle. Upon translocation of catenin-β1 into the nucleus, double-stranded DNA breaks were induced in transcriptionally active genes. Formation of R-loops was central to the induction of DNA cleavage. Selective induction of DNA cleavage rendered the affected cells more resistant to stressors by global modulation of the transcriptional profile of challenged cells. Further, mutations that arise subsequent to error-prone repair of DNA damage by non-homologous end-joining could accelerate clonal evolution of neoplastic cells after exposure to stressors and lead to emergence of resistant clonal populations. Findings demonstrate a novel mechanism for induction of dormancy that is conducive to accelerated emergence of neoplastic resistance