2207 MicroRNA-based single-cell CRISPR screens to discover microRNA-mRNA networks involved in carboplatin resistance in ovarian and lung cancer

Carboplatin is a platinum-based chemotherapy drug in lung and ovarian cancer treatment. Unfortunately, despite improved survival, numerous patients relapse and succumb to the disease because of carboplatin resistance. Therefore a further understanding of the evolutionary processes underlying resistance formation is crucial for developing effective treatments that are able to overcome resistance and cancer relapse. MicroRNAs (miRNAs) are small RNA molecules that repress post-transcriptional gene expression by interacting with the 3'UTR of mRNA targets. It has been shown that microRNAs are often involved in chemotherapy resistance in various cancers by regulating the important transcripts that code for proteins involved in this process. We hypothesize that cellular networks of miRNA-mRNA interactions are involved in carboplatin resistance in lung and ovarian cancer. Initially, to evaluate which miRNA-mRNA interaction confers resistance to carboplatin in lung and ovarian cancers, we will integrate miRNA and RNA sequencing in non-resistant and resistant cancer cell lines. These approaches will discover the miRNAs and potential targets that are dysregulated during chemoresistance. Furthermore, to understand their mechanism of action we will establish the first miRNA-based single-cell CRISPR screen to evaluate how selected carboplatin-resistance miRNA-mRNA networks act in carboplatin resistance at single-cell resolution. Important miRNA-mRNA interaction will be further validated by performing gold-standard biochemical experiments. The Discovery of miRNA-target networks involved in this process will provide new insights into the underlying evolutionary processes and, hence, into the principles of evolution as well as new therapeutic avenues to overcome lung and ovarian cancer relapse.