Epigenetic regulation of transcriptional heterogeneity controls cancer therapy resistance acquisition.

Cellular heterogeneity in tumors is an important and common underlying mechanism of resistance in cancer therapies. Identifying drivers of this heterogeneity will allow more targeted treatments to be developed for increasing therapy response in the long term. Recent advantages in single cell-omics enable us to measure cell-intrinsic stochastic heterogeneity. We hypothesise that this aspect of transcriptional heterogeneity is epigenetically regulated, and controls acquisition of therapy resistance. To test this hypothesis, we will combine CRISPR and epigenetic inhibitor screens with single cell RNA-seq, and measure how altering epigenetic enzyme activity affects stochastic and deterministic cellular heterogeneity. Next, the role of epigenetic drivers of heterogeneity in therapy response will be validated by assessing how they affect drug tolerance of cancer cells, and whether reducing heterogeneity curbs resistance acquisition. Lastly, I will also quantify the influence of defined “signatures of heterogeneity” on therapy outcome in patients. While I anticipate a pleiotropic impact, with several research domains standing to benefit, my long-term aim is to improve patient outcome by understanding the mechanisms that drive tumor heterogeneity.